Survey of diagnostic and treatment practices for multiple sclerosis (MS) in Europe. Part 2: Progressive MS, paediatric MS, pregnancy and general management.

PubMed

Fernández, O; Delvecchio, M; Edan, G; Fredrikson, S; Giovannoni, G; Hartung, H-P; Havrdova, E; Kappos, L; Pozzilli, C; Soerensen, P S; Tackenberg, B; Vermersch, P; Comi, G

2018-05-01

The European Charcot Foundation supported the development of a set of surveys to understand current practice patterns for the diagnosis and management of multiple sclerosis (MS) in Europe. Part 2 of the report summarizes survey results related to secondary progressive MS (SPMS), primary progressive MS (PPMS), pregnancy, paediatric MS and overall patient management. A steering committee of MS neurologists developed case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Respondents generally favoured changing rather than stopping disease-modifying treatment (DMT) in patients transitioning from relapsing-remitting MS to SPMS, particularly with active disease. Respondents would not initiate DMT in patients with typical PPMS symptoms, although the presence of ≥1 spinal cord or brain gadolinium-enhancing lesion might affect that decision. For patients considering pregnancy, respondents were equally divided on whether to stop treatment before or after conception. Respondents strongly favoured starting DMT in paediatric MS with active disease; recommended treatments included interferon, glatiramer acetate and, in John Cunningham virus negative patients, natalizumab. Additional results regarding practice-based questions and management are summarized. Results of part 2 of the survey of diagnostic and treatment practices for MS in Europe largely mirror results for part 1, with neurologists in general agreement about the treatment and management of SPMS, PPMS, pregnancy and paediatric MS as well as the general management of MS. However, there are also many areas of disagreement, indicating the need for evidence-based recommendations and/or guidelines. © 2018 EAN.

Staging of cortical and deep grey matter functional connectivity changes in multiple sclerosis.

PubMed

Meijer, Kim A; Eijlers, Anand J C; Geurts, Jeroen J G; Schoonheim, Menno M

2018-02-01

Functional connectivity is known to increase as well as decrease throughout the brain in multiple sclerosis (MS), which could represent different stages of the disease. In addition, functional connectivity changes could follow the atrophy pattern observed with disease progression, that is, moving from the deep grey matter towards the cortex. This study investigated when and where connectivity changes develop and explored their clinical and cognitive relevance across different MS stages. A cohort of 121 patients with early relapsing-remitting MS (RRMS), 122 with late RRMS and 53 with secondary progressive MS (SPMS) as well as 96 healthy controls underwent MRI and neuropsychological testing. Functional connectivity changes were investigated for (1) within deep grey matter connectivity, (2) connectivity between the deep grey matter and cortex and (3) within-cortex connectivity. A post hoc regional analysis was performed to identify which regions were driving the connectivity changes. Patients with late RRMS and SPMS showed increased connectivity of the deep grey matter, especially of the putamen and palladium, with other deep grey matter structures and with the cortex. Within-cortex connectivity was decreased, especially for temporal, occipital and frontal regions, but only in SPMS relative to early RRMS. Deep grey matter connectivity alterations were related to cognition and disability, whereas within-cortex connectivity was only related to disability. Increased connectivity of the deep grey matter became apparent in late RRMS and further increased in SPMS. The additive effect of cortical network degeneration, which was only seen in SPMS, may explain the sudden clinical deterioration characteristic to this phase of the disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Information processing speed and influential factors in multiple sclerosis].

PubMed

Zhang, M L; Xu, E H; Dong, H Q; Zhang, J W

2016-04-19

To study the information processing speed and the influential factors in multiple sclerosis (MS) patients. A total of 36 patients with relapsing-remitting MS (RRMS), 21 patients with secondary progressive MS (SPMS), and 50 healthy control subjects from Xuanwu Hospital of Capital Medical University between April 2010 and April 2012 were included into this cross-sectional study.Neuropsychological tests was conducted after the disease had been stable for 8 weeks, including information processing speed, memory, executive functions, language and visual perception.Correlation between information processing speed and depression, fatigue, Expanded Disability Status Scale (EDSS) were studied. (1)MS patient groups demonstrated cognitive deficits compared to healthy controls.The Symbol Digit Modalities Test (SDMT) (control group 57±12; RRMS group 46±17; SPMS group 35±10, P<0.05) and Paced Auditory Serial Addition Task (PASAT) (control group 85±18; RRMS group 77±20; SPMS group 57±20, P<0.05) impaired most.SPMS patients were more affected compared to patients with RRMS subtypes, and these differences were attenuated after control for physical disability level as measured by the EDSS scores.MS patients, especially SPMS subtype, were more severely impaired than control group in the verbal learning test, verbal fluency, Stroop C test planning time, while visual-spatial function and visual memory were relatively reserved in MS patients.(2) According to the Pearson univariate correlation analysis, age, depression, EDSS scores and fatigue were related with PASAT and SDMT tests (r=-0.41--0.61, P<0.05). Depression significantly affected the speed of information processing (P<0.05). Impairment of information processing speed, verbal memory and executive functioning are seen in MS patients, especially in SPMS subtype, while visual-spatial function is relatively reserved.Age, white matter change scales, EDSS scores, depression are negatively associated with information processing speed.

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

PubMed Central

Ifergan, Igal; Davidson, Todd S.; Kebir, Hania; Xu, Dan; Palacios-Macapagal, Daphne; Cann, Jennifer; Rodgers, Jane M.; Hunter, Zoe N.; Pittet, Camille L.; Beddow, Sara; Jones, Clare A.; Prat, Alexandre; Sleeman, Matthew A.; Miller, Stephen D.

2017-01-01

In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα+ myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. PMID:28641926

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity.

PubMed

Ifergan, Igal; Davidson, Todd S; Kebir, Hania; Xu, Dan; Palacios-Macapagal, Daphne; Cann, Jennifer; Rodgers, Jane M; Hunter, Zoe N; Pittet, Camille L; Beddow, Sara; Jones, Clare A; Prat, Alexandre; Sleeman, Matthew A; Miller, Stephen D

2017-11-01

In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα + myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. Copyright © 2017 Elsevier Ltd. All rights reserved.

'You are just left to get on with it': qualitative study of patient and carer experiences of the transition to secondary progressive multiple sclerosis.

PubMed

Davies, F; Edwards, A; Brain, K; Edwards, M; Jones, R; Wallbank, R; Robertson, N P; Wood, F

2015-07-22

Although the transition to secondary progressive multiple sclerosis (SPMS) is known to be a period of uncertainty for clinicians, who may find progressive disease challenging to objectively identify, little research has explored the experiences of patients and carers specifically during this transition period. Our objective was to explore what patients and their carers understand about their disease stage and describe their experiences and perspectives on the transition to SPMS. Semistructured qualitative interviews and subsequent validation focus groups were analysed using inductive thematic analysis. South East Wales, UK. 20 patients with MS and 13 carers were interviewed. Eight patients and two carers participated in focus groups. Four main themes around disease progression were identified. 'Realisation' describes how patients came to understand they had SPMS while 'reaction' describes their response to this realisation. The 'realities' of living with SPMS, including dealing with the healthcare system during this period, were described along with 'future challenges' envisaged by patients and carers. Awareness that the transition to SPMS has occurred, and subsequent emotional reactions and coping strategies, varied widely between patients and their carers. The process of diagnosing the transition was often not transparent and some individuals wanted information to help them understand what the transition to SPMS meant for them. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Deep gray matter volume loss drives disability worsening in multiple sclerosis

PubMed Central

Prados, Ferran; Brownlee, Wallace J.; Altmann, Daniel R.; Tur, Carmen; Cardoso, M. Jorge; De Angelis, Floriana; van de Pavert, Steven H.; Cawley, Niamh; De Stefano, Nicola; Stromillo, M. Laura; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A.; Rovira, Alex; Sastre‐Garriga, Jaume; Vrenken, Hugo; Leurs, Cyra E.; Killestein, Joep; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Wheeler‐Kingshott, Claudia A.M. Gandini; Chard, Declan; Thompson, Alan J.; Alexander, Daniel C.; Barkhof, Frederik; Ciccarelli, Olga

2018-01-01

Objective Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods We analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS], 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS]), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression. Results SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (–1.45%), PPMS (–1.66%), and RRMS (–1.34%) than CIS (–0.88%) and HCs (–0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (–1.21%) was significantly faster than RRMS (–0.76%), CIS (–0.75%), and HCs (–0.51%). Similarly, the rate of parietal GM atrophy in SPMS (–1.24‐%) was faster than CIS (–0.63%) and HCs (–0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). Interpretation This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210–222 PMID:29331092

Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis.

PubMed

Malyavantham, Kishore; Weinstock-Guttman, Bianca; Suresh, Lakshmanan; Zivadinov, Robert; Shanahan, Thomas; Badgett, Darlene; Ramanathan, Murali

2015-01-01

To compare frequencies of autoreactive antibody responses to endogenous disease-associated antigens in healthy controls (HC), relapsing and progressive MS and to assess their associations with clinical and MRI measures of MS disease progression. The study analyzed 969 serum samples from 315 HC, 411 relapsing remitting MS (RR-MS), 128 secondary progressive MS (SP-MS), 33 primary progressive MS (PP-MS) and 82 patients with other neurological diseases for autoantibodies against two putative MS antigens CSF114(Glc) and KIR4.1a and KIR4.1b and against 24 key endogenous antigens linked to diseases such as vasculitis, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polymyositis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease and primary biliary cirrhosis. Associations with disability and MRI measures of lesional injury and neurodegeneration were assessed. The frequencies of anti-KIR4.1a and anti-KIR4.1b peptide IgG positivity were 9.8% and 11.4% in HC compared to 4.9% and 7.5% in RR-MS, 8.6% for both peptides in SP-MS and 6.1% for both peptides in PP-MS (p = 0.13 for KIR4.1a and p = 0.34 for KIR4.1b), respectively. Antibodies against CSF114(Glc), KIR4.1a and KIR4.1b peptides were not associated with MS compared to HC, or with MS disease progression. HLA DRB1*15:01 positivity and anti-Epstein Barr virus antibodies, which are MS risk factors, were not associated with these putative MS antibodies. Antibody responses to KIR4.1a and KIR4.1b peptides are not increased in MS compared to HC nor associated with MS disease progression. The frequencies of the diverse autoreactive antibodies investigated are similar in MS and HC.

Patterns of white matter damage are non-random and associated with cognitive function in secondary progressive multiple sclerosis.

PubMed

Meijer, K A; Cercignani, M; Muhlert, N; Sethi, V; Chard, D; Geurts, J J G; Ciccarelli, O

2016-01-01

In multiple sclerosis (MS), white matter damage is thought to contribute to cognitive dysfunction, which is especially prominent in secondary progressive MS (SPMS). While studies in healthy subjects have revealed patterns of correlated fractional anisotropy (FA) across white matter tracts, little is known about the underlying patterns of white matter damage in MS. In the present study, we aimed to map the SPMS-related covariance patterns of microstructural white matter changes, and investigated whether or not these patterns were associated with cognitive dysfunction. Diffusion MRI was acquired from 30 SPMS patients and 32 healthy controls (HC). A tensor model was fitted and FA maps were processed using tract-based spatial statistics (TBSS) in order to obtain a skeletonised map for each subject. The skeletonised FA maps of patients only were decomposed into 18 spatially independent components (ICs) using independent component analysis. Comprehensive cognitive assessment was conducted to evaluate five cognitive domains. Correlations between cognitive performance and (1) severity of FA abnormalities of the extracted ICs (i.e. z-scores relative to FA values of HC) and (2) IC load (i.e. FA covariance of a particular IC) were examined. SPMS patients showed lower FA values of all examined patterns of correlated FA (i.e. spatially independent components) than HC (p < 0.01). Tracts visually assigned to the supratentorial commissural class were most severely damaged (z = - 3.54; p < 0.001). Reduced FA was significantly correlated with reduced IC load (i.e. FA covariance) (r = 0.441; p < 0.05). Lower mean FA and component load of the supratentorial projection tracts and limbic association tracts classes were associated with worse cognitive function, including executive function, working memory and verbal memory. Despite the presence of white matter damage, it was possible to reveal patterns of FA covariance across SPMS patients. This could indicate that white matter tracts belonging to the same cluster, and thus with similar characteristics, tend to follow similar trends during neurodegeneration. Furthermore, these underlying FA patterns might help to explain cognitive dysfunction in SPMS.

Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study

PubMed Central

2012-01-01

Background Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS). Methods Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%. Results Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups. Conclusion These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation. PMID:22691628

Mapping face encoding using functional MRI in multiple sclerosis across disease phenotypes.

PubMed

Rocca, Maria A; Vacchi, Laura; Rodegher, Mariaemma; Meani, Alessandro; Martinelli, Vittorio; Possa, Francesca; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

2017-10-01

Using fMRI during a face encoding (FE) task, we investigated the behavioral and fMRI correlates of FE in patients with relapse-onset multiple sclerosis (MS) at different stages of the disease and their relation with attentive-executive performance and structural MRI measures of disease-related damage. A fMRI FE task was administered to 75 MS patients (11 clinically isolated syndromes - CIS, 40 relapsing-remitting - RRMS - and 24 secondary progressive - SPMS) and 22 healthy controls (HC). fMRI activity during the face encoding condition was correlated with behavioral, clinical, neuropsychological and structural MRI variables. All study subjects activated brain regions belonging to face perception and encoding network, and deactivated areas of the default-mode network. Compared to HC, MS patients had the concomitant presence of areas of increased and decreased activations as well as increased and decreased deactivations. Compared to HC or RRMS, CIS patients experienced an increased recruitment of posterior-visual areas. Thalami, para-hippocampal gyri and right anterior cingulum were more activated in RRMS vs CIS or SPMS patients, while an increased recruitment of frontal areas was observed in SPMS vs RRMS. Areas of abnormal activations were significantly correlated with clinical, cognitive-behavioral and structural MRI measures. Abnormalities of FE network occur in MS and vary across disease clinical phenotypes. Early in the disease, an increased recruitment of areas typically devoted to face perception and encoding occurs. In SPMS patients, abnormal functional recruitment of frontal lobe areas might contribute to the severity of clinical manifestations.

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients.

PubMed

Atya, Hanaa B; Ali, Sahar A; Hegazy, Mohamed I; El Sharkawi, Fathia Z

2018-04-01

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.

Intracortical excitability in patients with relapsing-remitting and secondary progressive multiple sclerosis.

PubMed

Conte, A; Lenzi, D; Frasca, V; Gilio, F; Giacomelli, E; Gabriele, M; Bettolo, C Marini; Iacovelli, E; Pantano, P; Pozzilli, C; Inghilleri, M

2009-06-01

We designed this study to investigate possible correlations between variables measuring primary motor cortex excitability detected by single and paired-pulse transcranial magnetic stimulation (TMS) and the severity of clinical manifestations in patients with multiple sclerosis (MS). Thirty patients with MS in remission, 16 with relapsing-remitting (RR), 14 with secondary progressive disease (SP) and 17 healthy subjects participated in the study. In each subject, the central motor conduction time (CMCT) was calculated, and single-pulse and paired-pulse TMS at 3 and 10 ms interstimulus intervals was delivered over the primary motor cortex of the dominant hemisphere to measure the amplitude of motor-evoked potentials (MEPs), motor threshold (MTh), intracortical inhibition (ICI) and facilitation (ICF). Correlations were determined between the patients' TMS findings and magnetic resonance imaging (MRI) (lesion load) and clinical features (expanded disability status scale, EDSS score). EDSS scores were significantly higher in SPMS than in RRMS patients. The MTh was significantly higher, and the MEP was significantly smaller in SPMS patients than in RRMS patients and control subjects. All patients had longer CMCTs than healthy subjects. In all patients, paired-pulse TMS elicited an inhibited test MEP at the 3-ms ISI and a facilitated test MEP at the 10 ms ISI. Post hoc analysis showed that ICI was significantly lower in SPMS patients than in those with RRMS and healthy subjects. EDSS scores correlated significantly with TMS measures (MEP, ICI, CMCT and MTh), but not with MRI lesion load. It was found that intracortical excitability as measured with TMS differs according to the clinical course of MS; it remains normal in patients with low EDSS scores and is altered in patients with high EDSS scores.

Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis.

PubMed

Dogonowski, A-M; Siebner, H R; Soelberg Sørensen, P; Paulson, O B; Dyrby, T B; Blinkenberg, M; Madsen, K H

2013-11-01

To characterize the relationship between motor resting-state connectivity of the dorsal pre-motor cortex (PMd) and clinical disability in patients with multiple sclerosis (MS). A total of 27 patients with relapsing-remitting MS (RR-MS) and 15 patients with secondary progressive MS (SP-MS) underwent functional resting-state magnetic resonance imaging. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Independent component analysis was used to characterize motor resting-state connectivity. Multiple regression analysis was performed in SPM8 between the individual expression of motor resting-state connectivity in PMd and EDSS scores including age as covariate. Separate post hoc analyses were performed for patients with RR-MS and SP-MS. The EDSS scores ranged from 0 to 7 with a median score of 4.3. Motor resting-state connectivity of left PMd showed a positive linear relation with clinical disability in patients with MS. This effect was stronger when considering the group of patients with RR-MS alone, whereas patients with SP-MS showed no increase in coupling strength between left PMd and the motor resting-state network with increasing clinical disability. No significant relation between motor resting-state connectivity of the right PMd and clinical disability was detected in MS. The increase in functional coupling between left PMd and the motor resting-state network with increasing clinical disability can be interpreted as adaptive reorganization of the motor system to maintain motor function, which appears to be limited to the relapsing-remitting stage of the disease. © 2013 John Wiley & Sons A/S.

Adenosine Triphosphate Metabolism Measured by Phosphorus Magnetic Resonance Spectroscopy: A Potential Biomarker for Multiple Sclerosis Severity.

PubMed

Kauv, Paul; Ayache, Samar S; Créange, Alain; Chalah, Moussa A; Lefaucheur, Jean-Pascal; Hodel, Jérôme; Brugières, Pierre

2017-01-01

Phosphorus magnetic resonance spectroscopy (31P-MRS) has previously shown abnormal changes in energy metabolites in the brain of multiple sclerosis (MS) patients. However, the relationship between these energy metabolites - particularly adenosine triphosphate (ATP) - and the disease severity remains unclear. The objective of this study was to determine whether measuring ATP metabolites can help to predict disease severity in MS patients. 31P-MRS at 3 tesla was performed in 9 relapsing remitting (RRMS), 9 secondary progressive MS patients (SPMS), and 10 age-matched healthy controls. ATP metabolites (expressed as %) in normally appearing white matter of the centrum semiovale were compared between patients and healthy controls. The relationship between Expanded Disability Status Scale (EDSS) and ATP metabolites was evaluated. RRMS and SPMS patients had higher phosphocreatine (PCr) and lower phosphodiesters than healthy controls. In addition, RRMS patients had higher β-ATP% than SPMS patients. β-ATP% was negatively correlated with EDSS in all patients. Our findings suggest a defective PCr metabolism in both patient groups, and a higher state of energy production in RRMS that might reflect a compensatory mechanism in face of the increased needs. The correlation of β-ATP with EDSS makes it a candidate biomarker for assessing MS disease severity. © 2017 S. Karger AG, Basel.

Neuronal and BBB damage induced by sera from patients with secondary progressive multiple sclerosis.

PubMed

Proia, Patrizia; Schiera, Gabriella; Salemi, Giuseppe; Ragonese, Paolo; Savettieri, Giovanni; Di Liegro, Italia

2009-12-01

An important component of the pathogenic process of multiple sclerosis (MS) is the blood-brain barrier (BBB) damage. We recently set an in vitro model of BBB, based on a three-cell-type co-culture system, in which rat neurons and astrocytes synergistically induce brain capillary endothelial cells to form a monolayer with permeability properties resembling those of the physiological BBB. Herein we report that the serum from patients with secondary progressive multiple sclerosis (SPMS) has a damaging effect on isolated neurons. This finding suggests that neuronal damaging in MS could be a primary event and not only secondary to myelin damage, as generally assumed. SPMS serum affects the permeability of the BBB model, as indicated by the decrease of the transendothelial electrical resistance (TEER). Moreover, as shown by both immunofluorescence and Western blot analyses, BBB breaking is accompanied by a decrease of the synthesis as well as the peripheral localization of occludin, a structural protein of the tight junctions that are responsible for BBB properties.

Use of the PRIMUS scale to assess quality of life in a Spanish population of multiple sclerosis patients.

PubMed

Hernández, M A; Mora, S

2013-01-01

Symptoms of multiple sclerosis (MS) are associated with significant and progressive functional disability and have a profound impact on patients' quality of life (QoL). QoL and daily life activities are two areas that suffer major changes during the course of MS and there are currently no questionnaires specifically designed to evaluate these areas in MS patients. To evaluate QoL of MS patients using the PRIMUS questionnaire and determine the possible relationship between QoL, duration of disease, and disability measured on the EDSS. Multi-centre epidemiological and cross-sectional study including 261 patients with relapsing remitting MS (RRMS) or secondary progressive MS (SPMS) treated with interferon beta-1b for at least 6 months. The validated version of the PRIMUS questionnaire was used for patient reporting of changes in QoL and life activities. Mean age of patients was 41.7±10.3 years; 61.3% were women. Most had RRMS (83.9%). Mean time since MS diagnosis was 7.6±5.8 years, and longer in the SPMS group (11.2±7.4 vs 6.9±5.2, P<.0001). Mean EDSS score was 2.6±1.75 (5.1±1.3 in SPMS vs 2.1±1.4 in RRMS, P<.0001). Mean time since start of treatment was 5.5±3.8 years. The PRIMUS QoL component was higher in the RRMS group: 18.3±6.8 vs 9.9±7.1 (P<.0001); it also decreased with increases in both time since diagnosis (P<.01) and disability scores (from 18.8±6.6 in early stages [EDSS<3.5] to 8.4±6.3 in advanced stages [EDSS>5], P<.0001). The PRIMUS activity limitations component followed the same pattern: activity became more limited with increases in time since diagnosis (P<.0001) and overall disability (P<.0001). QoL in MS patients varies according to the disease type, and it worsens progressively over time and with increasing disability. The PRIMUS questionnaire is a good tool for assessing QoL and activity in patients with MS. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Employment and absenteeism in working-age persons with multiple sclerosis.

PubMed

Salter, Amber; Thomas, Nina; Tyry, Tuula; Cutter, Gary; Marrie, Ruth Ann

2017-05-01

To better understand the impact of the clinical course of multiple sclerosis (MS) and disability on employment, absenteeism, and related factors. This study included respondents to the North American Research Committee on Multiple Sclerosis Registry spring 2015 update survey who were US or Canadian residents, aged 18-65 years and reported having relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The RRMS and SPMS participants were combined to form the relapsing-onset MS (RMS) group and compared with the PPMS group regarding employment status, absenteeism, and disability. Multivariable logistic regression was used to examine the relationship between employment-related outcomes and factors that may affect these relationships. Of the 8004 survey respondents, 5887 (73.6%) were 18-65 years of age. The PPMS group (n = 344) had a higher proportion of males and older mean age at the time of the survey and at time of diagnosis than the RMS group (n = 4829). Female sex, age, age at diagnosis, cognitive and hand function impairment, fatigue, higher disability levels, ≥3 comorbidities, and a diagnosis of PPMS were associated with not working. After adjustment for disability, the employed PPMS sub-group reported similar levels of absenteeism to the employed RMS sub-group. Limitations of the study include self-report of information and the possibility that participants may not fully represent the working-age MS population. In MS, employment status and absenteeism are negatively affected by disability, cognitive impairment, and fatigue. These findings underscore the need for therapies that prevent disability progression and other symptoms that negatively affect productivity in persons with MS to enable them to persist in the workforce.

Smoking and multiple sclerosis: A systematic review and meta-analysis using the Bradford Hill criteria for causation.

PubMed

Degelman, Michelle L; Herman, Katya M

2017-10-01

Despite being one of the most common neurological disorders globally, the cause(s) of multiple sclerosis (MS) remain unknown. Cigarette smoking has been studied with regards to both the development and progression of MS. The Bradford Hill criteria for causation can contribute to a more comprehensive evaluation of a potentially causal risk factor-disease outcome relationship. The objective of this systematic review and meta-analysis was to assess the relationship between smoking and both MS risk and MS progression, subsequently applying Hill's criteria to further evaluate the likelihood of causal associations. The Medline, EMBASE, CINAHL, PsycInfo, and Cochrane Library databases were searched for relevant studies up until July 28, 2015. A random-effects meta-analysis was conducted for three outcomes: MS risk, conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), and progression from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS). Dose-response relationships and risk factor interactions, and discussions of mechanisms and analogous associations were noted. Hill's criteria were applied to assess causality of the relationships between smoking and each outcome. The effect of second-hand smoke exposure was also briefly reviewed. Smoking had a statistically significant association with both MS risk (conservative: OR/RR 1.54, 95% CI [1.46-1.63]) and SPMS risk (HR 1.80, 95% CI [1.04-3.10]), but the association with progression from CIS to CDMS was non-significant (HR 1.13, 95% CI [0.73-1.76]). Using Hill's criteria, there was strong evidence of a causal role of smoking in MS risk, but only moderate evidence of a causal association between smoking and MS progression. Heterogeneity in study designs and target populations, inconsistent results, and an overall scarcity of studies point to the need for more research on second-hand smoke exposure in relation to MS prior to conducting a detailed meta-analysis. This first review to supplement systematic review and meta-analytic methods with Hill's criteria to analyze the smoking-MS association provides evidence supporting the causal involvement of smoking in the development and progression of MS. Smoking prevention and cessation programs and policies should consider MS as an additional health risk when aiming to reduce smoking prevalence in the population. Copyright © 2017 Elsevier B.V. All rights reserved.

Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication.

PubMed

Festoff, Barry W; Li, Chaoyang; Woodhams, Barry; Lynch, Sharon

2012-12-15

Thrombomodulin (TM) on the cell-surface of cerebrovascular endothelial cells (CECs) is released into blood upon CEC damage. TM promotes activation of protein C (APC), an anticoagulant, anti-inflammatory, neuroprotective molecule that protects CECs and impedes inflammatory cell migration across the blood-brain barrier (BBB). Multiple sclerosis (MS) is associated with CEC damage and BBB dysfunction. We evaluated soluble TM (sTM) levels as a biomarker of BBB integrity and whether glatiramer acetate (GA) influenced sTM levels in MS patients. sTM levels quantified by 2-site ELISA from sera of healthy controls and systemic lupus erythematosus (SLE) patients (CEC-damage positive control) were compared with levels from patients with relapsing-remitting (RRMS) or secondary-progressive MS (SPMS), stratified as: RRMS/GA/no relapse, RRMS/GA/in relapse, RRMS no GA/no relapse, RRMS/no GA/in relapse; and SPMS/no GA. Additionally, soluble endothelial protein C receptor (sEPCR) levels were assessed in the non-stratified MS group, SLE patients, and controls. sTM levels were highest in RRMS patients taking GA with or without relapse, followed in decreasing order by SLE, RRMS/no GA/in relapse, SPMS, RRMS/no GA/no relapse, healthy controls. sEPCR levels were highest in MS patients, then SLE, then controls. sTM may be a useful biomarker of BBB integrity in RRMS patients. Further evaluation of sEPCR is needed. The finding that the highest sTM levels were in RRMS patients taking GA is interesting and warrants further investigation. Published by Elsevier B.V.

Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes.

PubMed

Rocca, Maria A; Valsasina, Paola; Damjanovic, Dusan; Horsfield, Mark A; Mesaros, Sarlota; Stosic-Opincal, Tatjana; Drulovic, Jelena; Filippi, Massimo

2013-01-01

To apply voxel-based methods to map the regional distribution of atrophy and T2 hyperintense lesions in the cervical cord of multiple sclerosis (MS) patients with different clinical phenotypes. Brain and cervical cord 3D T1-weighted and T2-weighted scans were acquired from 31 healthy controls (HC) and 77 MS patients (15 clinically isolated syndromes (CIS), 15 relapsing-remitting (RR), 19 benign (B), 15 primary progressive (PP) and 13 secondary progressive (SP) MS). Hyperintense cord lesions were outlined on T2-weighted scans. The T2- and 3D T1-weighted cord images were then analysed using an active surface method which created output images reformatted in planes perpendicular to the estimated cord centre line. These unfolded cervical cord images were co-registered into a common space; then smoothed binary cord masks and lesion masks underwent spatial statistic analysis (SPM8). No cord atrophy was found in CIS patients versus HC, while PPMS had significant cord atrophy. Clusters of cord atrophy were found in BMS versus RRMS, and in SPMS versus RRMS, BMS and PPMS patients, mainly involving the posterior and lateral cord segments. Cord lesion probability maps showed a significantly greater likelihood of abnormalities in RRMS, PPMS and SPMS than in CIS and BMS patients. The spatial distributions of cord atrophy and cord lesions were not correlated. In progressive MS, regional cord atrophy was correlated with clinical disability and impairment in the pyramidal system. Voxel-based assessment of cervical cord damage is feasible and may contribute to a better characterisation of the clinical heterogeneity of MS patients.

Determining Multiple Sclerosis Phenotype from Electronic Medical Records.

PubMed

Nelson, Richard E; Butler, Jorie; LaFleur, Joanne; Knippenberg, Kristin; C Kamauu, Aaron W; DuVall, Scott L

2016-12-01

Multiple sclerosis (MS), a central nervous system disease in which nerve signals are disrupted by scarring and demyelination, is classified into phenotypes depending on the patterns of cognitive or physical impairment progression: relapsing-remitting MS (RRMS), primary-progressive MS (PPMS), secondary-progressive MS (SPMS), or progressive-relapsing MS (PRMS). The phenotype is important in managing the disease and determining appropriate treatment. The ICD-9-CM code 340.0 is uninformative about MS phenotype, which increases the difficulty of studying the effects of phenotype on disease. To identify MS phenotype using natural language processing (NLP) techniques on progress notes and other clinical text in the electronic medical record (EMR). Patients with at least 2 ICD-9-CM codes for MS (340.0) from 1999 through 2010 were identified from nationwide EMR data in the Department of Veterans Affairs. Clinical experts were interviewed for possible keywords and phrases denoting MS phenotype in order to develop a data dictionary for NLP. For each patient, NLP was used to search EMR clinical notes, since the first MS diagnosis date for these keywords and phrases. Presence of phenotype-related keywords and phrases were analyzed in context to remove mentions that were negated (e.g., "not relapsing-remitting") or unrelated to MS (e.g., "RR" meaning "respiratory rate"). One thousand mentions of MS phenotype were validated, and all records of 150 patients were reviewed for missed mentions. There were 7,756 MS patients identified by ICD-9-CM code 340.0. MS phenotype was identified for 2,854 (36.8%) patients, with 1,836 (64.3%) of those having just 1 phenotype mentioned in their EMR clinical notes: 1,118 (39.2%) RRMS, 325 (11.4%) PPMS, 374 (13.1%) SPMS, and 19 (0.7%) PRMS. A total of 747 patients (26.2%) had 2 phenotypes, the most common being 459 patients (16.1%) with RRMS and SPMS. A total of 213 patients (7.5%) had 3 phenotypes, and 58 patients (2.0%) had 4 phenotypes mentioned in their EMR clinical notes. Positive predictive value of phenotype identification was 93.8% with sensitivity of 94.0%. Phenotype was documented for slightly more than one third of MS patients, an important but disappointing finding that sets a limit on studying the effects of phenotype on MS in general. However, for cases where the phenotype was documented, NLP accurately identified the phenotypes. Having multiple phenotypes documented is consistent with disease progression. The most common misidentification was because of ambiguity while clinicians were trying to determine phenotype. This study brings attention to the need for care providers to document MS phenotype more consistently and provides a solution for capturing phenotype from clinical text. This study was funded by Anolinx and F. Hoffman-La Roche. Nelson serves as a consultant for Anolinx. Kamauu is owner of Anolinx, which has received multiple research grants from pharmaceutical and biotechnology companies. LaFleur has received a Novartis grant for ongoing work. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. Study concept and design were contributed by Butler, LaFleur, Kamauu, DuVall, and Nelson. DuVall collected the data, and interpretation was performed by Nelson, DuVall, and Kamauu, along with Butler, LaFleur, and Knippenberg. The manuscript was written primarily by Nelson, along with Knippenberg and assisted by the other authors, and revised by Knippenberg, Nelson, and DuVall, along with the other authors.

A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

PubMed Central

D’Amico, Emanuele; Patti, Francesco; Zanghì, Aurora; Zappia, Mario

2016-01-01

Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several measures of risk estimation were developed for predicting clinical course in MS, but none is specific for the PMS forms. Personalized medicine is a therapeutic approach, based on identifying what might be the best therapy for an individual patient, taking into account the risk profile. We need to achieve more accurate estimates of useful predictors in PMS, including unconventional and qualitative markers which are not yet currently available or practicable routine diagnostics. The evaluation of an individual patient is based on the profile of disease activity.Within the neurology field, PMS is one of the fastest-moving going into the future. PMID:27763513

Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study.

PubMed

Dobryakova, Ekaterina; Rocca, Maria Assunta; Valsasina, Paola; Ghezzi, Angelo; Colombo, Bruno; Martinelli, Vittorio; Comi, Giancarlo; DeLuca, John; Filippi, Massimo

2016-06-01

The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing-remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal → dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula → left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293-2304, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Lipoic acid in secondary progressive MS

PubMed Central

Powers, Katherine; Murchison, Charles; Heriza, Elizabeth; Winges, Kimberly; Yadav, Vijayshree; Cameron, Michelle; Kim, Ed; Horak, Fay; Simon, Jack; Bourdette, Dennis

2017-01-01

Objective: To determine whether lipoic acid (LA), an endogenously produced antioxidant, slowed the whole-brain atrophy rate and was safe in secondary progressive MS (SPMS). Methods: Patients with SPMS aged 40–70 years enrolled in a single center, 2-year, double-blind, randomized trial of daily oral 1,200 mg LA vs placebo. Primary outcome was change in annualized percent change brain volume (PCBV). Secondary outcomes were changes in rates of atrophy of segmented brain, spinal cord, and retinal substructures, disability, quality of life, and safety. Intention-to-treat analysis used linear mixed models. Results: Participation occurred between May 2, 2011, and August 14, 2015. Study arms of LA (n = 27) and placebo (n = 24) were matched with mean age of 58.5 (SD 5.9) years, 61% women, mean disease duration of 29.6 (SD 9.5) years, and median Expanded Disability Status Score of 6.0 (interquartile range 1.75). After 2 years, the annualized PCBV was significantly less in the LA arm compared with placebo (−0.21 [standard error of the coefficient estimate (SEE) 0.14] vs −0.65 [SEE 0.10], 95% confidence interval [CI] 0.157–0.727, p = 0.002). Improved Timed 25-Foot Walk was almost but not significantly better in the LA than in the control group (−0.535 [SEE 0.358] vs 0.137 [SEE 0.247], 95% CI −1.37 to 0.03, p = 0.06). Significantly more gastrointestinal upset and fewer falls occurred in LA patients. Unexpected renal failure (n = 1) and glomerulonephritis (n = 1) occurred in the LA cohort. Compliance, measured by pill counts, was 87%. Conclusions: LA demonstrated a 68% reduction in annualized PCBV and suggested a clinical benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years. ClinicalTrials.gov identifier: NCT01188811. Classification of evidence: This study provides Class I evidence that for patients with SPMS, LA reduces the rate of brain atrophy. PMID:28680916

Reserve-building activities in multiple sclerosis patients and healthy controls: a descriptive study.

PubMed

Schwartz, Carolyn E; Ayandeh, Armon; Ramanathan, Murali; Benedict, Ralph; Dwyer, Michael G; Weinstock-Guttman, Bianca; Zivadinov, Robert

2015-08-12

Cognitive reserve has been implicated as a possible protective factor in multiple sclerosis (MS) but to date no study has compared reserve-building activities across disease course or to healthy controls. This study aims to describe differences in reserve-building activities across the MS disease course and healthy controls. Secondary analysis of a cross-sectional cohort study that included 276 healthy controls, and subjects with clinically isolated syndrome (CIS; n = 67), relapsing-remitting MS (RRMS; n = 358) and secondary progressive MS (PMS; n = 109). Past reserve-building activities were operationalized as occupational attainment and education. Current activities comprised 6 strenuous and 6 non-strenuous activities, including 5 reserve-building activities and television-watching. Multivariate Analysis of Variance models examined group differences in past and current activities, after adjusting for covariates. There were group differences in past and current reserve-building activities. SPMS patients had lower past reserve-building activities than healthy controls. All forms of MS engaged in fewer strenuous current reserve-building pursuits than healthy controls. RRMS read less than healthy controls. SPMS engaged in fewer job-related non-strenuous activities. All MS groups watched more television than healthy controls. MS patients show significantly fewer past and present reserve-building activities. Although it is difficult to establish causality without future prospective studies, lifestyle-modifying interventions should prioritize expanding MS patients' repertoire of strenuous and non-strenuous activities.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

PubMed

Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

PubMed

Jakimovski, Dejan; Weinstock-Guttman, Bianca; Ramanathan, Murali; Kolb, Channa; Hojnacki, David; Minagar, Alireza; Zivadinov, Robert

2017-09-01

Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

Characteristics, burden of illness, and physical functioning of patients with relapsing-remitting and secondary progressive multiple sclerosis: a cross-sectional US survey.

PubMed

Gross, Hillary J; Watson, Crystal

2017-01-01

Although most patients with relapsing-remitting multiple sclerosis (RRMS) will develop secondary progressive multiple sclerosis (SPMS), little is known about the burden of multiple sclerosis by disease subtype. This study describes the burden of disease in terms of demographics, disease severity, symptoms, health care resource and disease-modifying therapy (DMT) utilization, work and activity impairment, and physical functioning of SPMS and RRMS patients. SPMS and RRMS patient responses from the 2012 and 2013 waves of the US National Health and Wellness Survey were evaluated to detect differences in demographics, disease severity, symptoms, and health care resource and DMT utilization. In addition, data from the Work Productivity and Activity Impairment and Short Form-36 questionnaires were analyzed. SPMS patients were older than RRMS patients (mean age 55.7 vs 48.9 years; P <0.001); a lower proportion were female (56.2% with SPMS vs 71.6% with RRMS; P =0.002), and fewer SPMS than RRMS patients were employed (20.0% vs 39.7%; P <0.001). SPMS patients described their disease as more severe, reporting several neurological symptoms more frequently and higher hospitalization rates than RRMS patients. A lower percentage of SPMS than RRMS patients reported DMT use. SPMS patients had greater overall work and activity impairment than RRMS patients. After controlling for baseline characteristics, impairment in physical functioning was greater in SPMS patients. Overall, SPMS patients had a higher burden of illness than RRMS patients, underscoring the need to treat RRMS patients early to delay disability progressing using therapies that are effective in real-world settings.

Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis.

PubMed

Amor, Sandra; van der Star, Baukje J; Bosca, Isabel; Raffel, Joel; Gnanapavan, Sharmilee; Watchorn, Jonathan; Kuhle, Jens; Giovannoni, Gavin; Baker, David; Malaspina, Andrea; Puentes, Fabiola

2014-09-01

Increased levels of antibodies to neurofilament light protein (NF-L) in biological fluids have been found to reflect neuroinflammatory responses and neurodegeneration in multiple sclerosis (MS). To evaluate whether levels of serum antibodies against NF-L correlate with clinical variants and treatment response in MS. The autoantibody reactivity to NF-L protein was tested in serum samples from patients with relapsing-remitting MS (RRMS) (n=22) and secondary progressive MS (SPMS) (n=26). Two other cohorts of RRMS patients under treatment with natalizumab were analysed cross-sectionally (n=16) and longitudinally (n=24). The follow-up samples were taken at 6, 12, 18 and 24 months after treatment, and the NF-L antibody levels were compared against baseline levels. NF-L antibodies were higher in MS clinical groups than healthy controls and in RRMS compared to SPMS patients (p<0.001). NF-L antibody levels were lower in natalizumab treated than in untreated patients (p<0.001). In the longitudinal series, NF-L antibody levels decreased over time and a significant difference was found following 24 months of treatment compared with baseline measurements (p=0.001). Drug efficacy in MS treatment indicates the potential use of monitoring the content of antibodies against the NF-L chain as a predictive biomarker of treatment response in MS. © The Author(s) 2014.

The Italian validation of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) and the application of the Cognitive Impairment Index scoring procedure in MS patients.

PubMed

Argento, Ornella; Incerti, Chiara C; Quartuccio, Maria E; Magistrale, Giuseppe; Francia, Ada; Caltagirone, Carlo; Pisani, Valerio; Nocentini, Ugo

2018-04-27

Cognitive dysfunction occurs in almost 50-60% of patients with multiple sclerosis (MS) even in early stages of the disease and affects different aspects of patient's life. Aims of the present study were (1) to introduce and validate an Italian version of the minimal assessment of cognitive functions in MS (MACFIMS) battery and (2) to propose the use of the Cognitive Impairment Index (CII) as a scoring procedure to define the degree of impairment in relapsing-remitting (RRMS) and secondary-progressive (SPMS) patients. A total of 240 HC and 123 MS patients performed the Italian version of the MACFIMS composed by the same tests as the original except for the Paced Auditory Serial Addition Test. The CII was derived for each score of the 11 scales for participants of both groups. The results of the study show that cognitive impairment affects around 50% of our sample of MS patients. In RRMS group, only the 15.7% of patients reported a severe impairment, while in the group of SPMS, the 51.4% of patients felt in the "severely impaired" group. Results are in line with previously reported percentages of impairment in MS patients, showing that the calculation of the CII applied to the Italian version of the MACFIMS is sensitive and reliable in detecting different degrees of impairment in MS patients.

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

PubMed

Cohen, Jeffrey A; Imrey, Peter B; Planchon, Sarah M; Bermel, Robert A; Fisher, Elizabeth; Fox, Robert J; Bar-Or, Amit; Sharp, Susan L; Skaramagas, Thomai T; Jagodnik, Patricia; Karafa, Matt; Morrison, Shannon; Reese Koc, Jane; Gerson, Stanton L; Lazarus, Hillard M

2018-04-01

Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10 6 MSCs/kg were thawed and administered IV. In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 10 6 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

Intrathecal IgM index correlates with a severe disease course in multiple sclerosis: Clinical and MRI results.

PubMed

Ozakbas, Serkan; Cinar, Bilge Piri; Özcelik, Pinar; Baser, Hatice; Kosehasanoğullari, Gorkem

2017-09-01

Intrathecally synthesized IgM can be seen not only in the cerebrospinal fluid (CSF) in infectious and inflammatory diseases of the central nervous system, but also in that of patients with multiple sclerosis (MS). Intrathecal IgM synthesis in MS seems to be correlated with an unfavorable disease course. In one cross-sectional study, intrathecal synthesis of IgM (IgM index) was found to be correlated with cranial magnetic resonance imaging (MRI) parameters. The purpose of this study was to determine the possible relationship between the IgM index and MRI and clinical parameters. Eighty-one patients with MS (58 female) undergoing lumbar puncture were included in the study. Fifty-one patients had a relapsing-remitting (RR) disease course, while 30 cases were secondary progressive MS (SPMS). IgM was detected in paired CSF and serum specimens using ELISA. The IgM index was calculated using the formula CSF IgM/serum IgM: CSF albumin/serum albumin. IgM indexes higher than 0.1 were considered "increased". All patients underwent brain and whole spinal cord MRI. The IgM index was normal in 43 of the 81 patients (53.1%) and increased in 38 (46.9%). A significant correlation was determined between the IgM index and Expanded Disability Status Scale (EDSS) (r=0.638, p=0.001). Most of the subjects with increased IgM indexes were SPMS patients, 28 having a SPMS course and 10 a RRMS course. Only two patients with SPMS courses had normal IgM indexes. EDSS scores were significantly higher in patients with increased IgM indexes (EDSS 4.3 vs EDSS 2.8, p=0.000). All patients with EDSS >3 had increased IgM indexes. All patients with IgM index values higher than 0.2 IgM had SPMS courses and EDSS >6. Time to onset of the secondary progressive phase of the disease was correlated with IgM index values (p=0.004). IgM index values were also correlated with T1 hypointense lesions (r=0.0431, p=0.008) and Gd enhancing lesions (r=0.0396, p=0.006). Patients with increased IgM indexes also had more spinal lesions (p=0.000). No relation was determined between an increased IgM index and an increased IgG index. No relation was determined with IgG oligoclonal band positivity. No correlation was also observed between IgM index and IgG index values. According to our findings, intrathecal IgM synthesis is associated with a worse long-term prognosis. It also correlates with a higher relapse rate, greater disability, and worse MRI outcomes. Early observation of increased IgM index values will be a helpful tool for clinicians in selecting patients for early immunomodulatory or immunosuppressant treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

Characteristics of lesional and extra-lesional cortical grey matter in relapsing-remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study.

PubMed

Yaldizli, Özgür; Pardini, Matteo; Sethi, Varun; Muhlert, Nils; Liu, Zheng; Tozer, Daniel J; Samson, Rebecca S; Wheeler-Kingshott, Claudia Am; Yousry, Tarek A; Miller, David H; Chard, Declan T

2016-02-01

In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. Seventy-two people with MS (46 relapsing-remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability. © The Author(s), 2015.

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

PubMed

Azodi, Shila; Nair, Govind; Enose-Akahata, Yoshimi; Charlip, Emily; Vellucci, Ashley; Cortese, Irene; Dwyer, Jenifer; Billioux, B Jeanne; Thomas, Chevaz; Ohayon, Joan; Reich, Daniel S; Jacobson, Steven

2017-11-01

Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. All spinal cord regions are thinner in HAM/TSP (56 mm 2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8 + T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728. © 2017 American Neurological Association.

A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS.

PubMed

Freedman, M S; Bar-Or, A; Oger, J; Traboulsee, A; Patry, D; Young, C; Olsson, T; Li, D; Hartung, H-P; Krantz, M; Ferenczi, L; Verco, T

2011-10-18

To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leukocyte antigen (HLA) haplotype DR2 or DR4 (DR2(+) or DR4(+)). This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5-6.5, stratified according to baseline EDSS score (3.5-5.0, or 5.5-6.5) and HLA haplotype (DR2(+) or DR4(+), or DR2(-)/DR4(-)). Upon entry of 100 DR2(-)/DR4(-) subjects, further study enrollment was limited to DR2(+) or DR4(+) subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by IV injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life. There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified. In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).

The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis.

PubMed

Scalfari, Antonio; Romualdi, Chiara; Nicholas, Richard S; Mattoscio, Miriam; Magliozzi, Roberta; Morra, Aldo; Monaco, Salvatore; Muraro, Paolo A; Calabrese, Massimiliano

2018-05-16

To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP. Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy. © 2018 American Academy of Neurology.

Neuroinflammatory component of gray matter pathology in multiple sclerosis.

PubMed

Herranz, Elena; Giannì, Costanza; Louapre, Céline; Treaba, Constantina A; Govindarajan, Sindhuja T; Ouellette, Russell; Loggia, Marco L; Sloane, Jacob A; Madigan, Nancy; Izquierdo-Garcia, David; Ward, Noreen; Mangeat, Gabriel; Granberg, Tobias; Klawiter, Eric C; Catana, Ciprian; Hooker, Jacob M; Taylor, Norman; Ionete, Carolina; Kinkel, Revere P; Mainero, Caterina

2016-11-01

In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11 C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Fifteen secondary-progressive MS (SPMS) patients, 12 relapsing-remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11 C-PBR28 MR-PET. MS subjects underwent 7T T2*-weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11 C-PBR28 binding was measured using normalized 60- to 90-minute standardized uptake values and volume of distribution ratios. Relative to controls, MS subjects exhibited abnormally high 11 C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11 C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11 C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776-790. © 2016 American Neurological Association.

Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure

PubMed Central

Sumowski, James F.; Leavitt, Victoria M.

2014-01-01

Objective To investigate whether resting body temperature is elevated and linked to fatigue in patients with relapsing-remitting multiple sclerosis (RRMS). Design Cross-sectional study investigating (a) differences in resting body temperature across RRMS, SPMS, and healthy groups, and (b) the relationship between body temperature and fatigue in RRMS patients. Setting Climate-controlled laboratory (~22°C) within a non-profit medical rehabilitation research center. Participants Fifty patients with RRMS, 40 matched healthy controls, and 22 patients with secondary-progressive MS (SPMS). Intervention None. Main Outcome Measure(s) Body temperature was measured with an aural infrared thermometer (normal body temperature for this thermometer is 36.75°C), and differences were compared across RRMS, SPMS, and healthy persons. RRMS patients completed measures of general fatigue (Fatigue Severity Scale; FSS), as well as physical and cognitive fatigue (Modified Fatigue Impact Scale; MFIS). Results There was a large effect of group (p<.001, ηp2=.132) whereby body temperature was higher in RRMS patients (37.04°C±0.27) relative to healthy controls (36.83 ± 0.33; p = .009) and SPMS patients (36.75°C±0.39; p=.001). Warmer body temperature in RRMS patients was associated with worse general fatigue (FSS; rp=.315, p=.028) and physical fatigue (pMFIS; rp=.318, p=.026), but not cognitive fatigue (cMIFS; rp=−.017, p=.909). Conclusions These are the first-ever demonstrations that body temperature is elevated endogenously in RRMS patients, and linked to worse fatigue. We discuss these findings in the context of failed treatments for fatigue in RRMS, including several failed randomized controlled trials (RCTs) of stimulants (modafinil). In contrast, our findings may help explain how RCTs of cooling garments and antipyretics (aspirin) have effectively reduced MS fatigue, and encourage further research on cooling/antipyretic treatments of fatigue in RRMS. PMID:24561056

Pro-resolution therapeutics for cardiovascular diseases.

PubMed

Heinz, Justin; Marinello, Michael; Fredman, Gabrielle

2017-09-01

Studies over the last couple of decades suggest that failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Resolution of inflammation is mediated in part by lipid-derived specialized pro-resolving mediators (SPMs) such as lipoxins, resolvins, protectins and maresins. The major functions of SPMs are to quell inflammation and repair tissue damage in a manner that does not compromise host defense. An imbalance between SPMs and pro-inflammatory mediators like leukotriene B 4 (LTB 4 ) are associated with several prevalent human diseases, including atherosclerosis. Because atherosclerosis is marked by persistent, unresolved inflammation and arterial tissue injury, SPMs have garnered immense interest as a potential treatment strategy. This mini review will highlight recent advances in the application of SPMs in atherosclerosis as well as the ability of SPMs to control several of the risk factors associated with cardiovascular diseases. Copyright © 2017. Published by Elsevier Inc.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

PubMed

Casanova, Bonaventura; Jarque, Isidro; Gascón, Francisco; Hernández-Boluda, Juan Carlos; Pérez-Miralles, Francisco; de la Rubia, Javier; Alcalá, Carmen; Sanz, Jaime; Mallada, Javier; Cervelló, Angeles; Navarré, Arantxa; Carcelén-Gadea, María; Boscá, Isabel; Gil-Perotin, Sara; Solano, Carlos; Sanz, Miguel Angel; Coret, Francisco

2017-07-01

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics.

PubMed

English, Justin T; Norris, Paul C; Hodges, Robin R; Dartt, Darlene A; Serhan, Charles N

2017-02-01

Specialized pro-resolving mediators (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A₄, and Resolvin E1 have each shown to be active in ocular models reducing inflammation. In general, SPMs have specific agonist functions that stimulate resolution of infection and inflammation in animal disease models. The presence and quantity of SPM in human emotional tears is of interest. Here, utilizing a targeted LC-MS-MS metabololipidomics based approach we document the identification of pro-inflammatory (Prostaglandins and Leukotriene B₄) and pro-resolving lipid mediators (D-series Resolvins, Protectin D1, and Lipoxin A₄) in human emotional tears from 12 healthy individuals. SPMs from the Maresin family (Maresin 1 and Maresin 2) were not present in these samples. Principal Component Analysis (PCA) revealed gender differences in the production of specific mediators within these tear samples as the SPMs were essentially absent in these female donors. These results indicate that specific SPM signatures are present in human emotional tears at concentrations known to be bioactive. Moreover, they will help to further appreciate the mechanisms of production and action of SPMs in the eye, as well as their physiologic roles in human ocular disease resolution. Copyright © 2017 Elsevier Ltd. All rights reserved.

Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation.

PubMed

Barden, Anne; Mas, Emilie; Croft, Kevin D; Phillips, Michael; Mori, Trevor A

2014-11-01

Resolution of inflammation is an active process involving specialized proresolving mediators (SPM) formed from the n-3 fatty acids. This study examined the effect of n-3 fatty acid supplementation and aspirin on plasma SPMs in healthy humans. Healthy volunteers (n = 21) were supplemented with n-3 fatty acids (2.4g/day) for 7 days with random assignment to take aspirin (300 mg/day) or placebo from day 5 to day 7. Blood was collected at baseline (day 0), day 5, and day 7. Plasma 18R/S-HEPE, E-series resolvins, 17R/S-HDHA, D-series resolvins, 14R/S-HDHA, and MaR-1 were measured by LC/MS/MS. At baseline concentrations of E- and D- series resolvins and the upstream precursors 18R/S-HEPE, 17R/S-HDHA ranged from 0.1nM to 0.2nM. 14R/S-HDHA was 3-fold higher than the other SPMs at baseline but MaR-1 was below the limit of detection. Supplementation with n-3 fatty acids significantly increased RvE1, 18R/S-HEPE, 17R/S-HDHA, and 14R/S-HDHA but not other SPMs. The addition of aspirin after 5 days of n-3 fatty acids did not affect concentrations of any SPM. N-3 fatty acid supplementation for 5 days results in concentrations of SPMs that are biologically active in healthy humans. Aspirin administered after n-3 fatty acids did not offer any additional benefit in elevating the levels of SPMs. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure.

PubMed

Sumowski, James F; Leavitt, Victoria M

2014-07-01

To investigate whether (1) resting body temperature is elevated in patients with relapsing-remitting multiple sclerosis (RRMS) relative to healthy individuals and patients with secondary progressive multiple sclerosis (SPMS), and (2) warmer body temperature is linked to worse fatigue in patients with RRMS. Cross-sectional study. Climate-controlled laboratory (∼22°C) within a nonprofit medical rehabilitation research center. Patients with RRMS (n=50), matched healthy controls (n=40), and patients with SPMS (n=22). Not applicable. Body temperature was measured with an aural infrared thermometer (normative body temperature for this thermometer, 36.75°C), and differences were compared across patients with RRMS and SPMS and healthy persons. Patients with RRMS completed measures of general fatigue (Fatigue Severity Scale [FSS]), as well as physical and cognitive fatigue (Modified Fatigue Impact Scale [MFIS]). There was a large effect of group (P<.001, ηp(2)=.132) whereby body temperature was higher in patients with RRMS (37.04°±.27°C) relative to healthy controls (36.83°±.33°C; P=.009) and patients with SPMS (36.75°±.39°C; P=.001). Warmer body temperature in patients with RRMS was associated with worse general fatigue (FSS; rp=.315, P=.028) and physical fatigue (physical fatigue subscale of the MFIS; rp=.318, P=.026), but not cognitive fatigue (cognitive fatigue subscale of the MIFS; rp=-.017, P=.909). These are the first-ever demonstrations that body temperature is elevated endogenously in patients with RRMS and linked to worse fatigue. We discuss these findings in the context of failed treatments for fatigue in RRMS, including several failed randomized controlled trials (RCTs) of stimulants (modafinil). In contrast, our findings may help explain how RCTs of cooling garments and antipyretics (aspirin) have effectively reduced MS fatigue, and encourage further research on cooling/antipyretic treatments of fatigue in RRMS. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.

PubMed

Chan, Dennis; Binks, Sophie; Nicholas, Jennifer M; Frost, Chris; Cardoso, M Jorge; Ourselin, Sebastien; Wilkie, David; Nicholas, Richard; Chataway, Jeremy

2017-08-01

In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6-7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8-8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2-2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3-4·8; p=0·028). A treatment effect was not noted for any other outcomes. To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Managing the transition (ManTra): a resource for persons with secondary progressive multiple sclerosis and their health professionals: protocol for a mixed-methods study in Italy

PubMed Central

Giordano, Andrea; Pietrolongo, Erika; Confalonieri, Paolo; De Luca, Giovanna; Tortorella, Carla; Trojano, Maria; Messmer Uccelli, Michele; Torri Clerici, Valentina; Gitto, Lara; Köpke, Sascha; Borreani, Claudia; Heesen, Christoph; Solari, Alessandra

2017-01-01

Introduction 15 years after clinical onset, about 50% of patients with relapsing-remitting multiple sclerosis convert to secondary progressive multiple sclerosis (SPMS). Notwithstanding the importance of this transition, knowledge of the experiences and needs of patients and carers is fragmentary, and targeted interventions are not available. Managing the Transition to SPMS (ManTra) is a mixed methodology project to develop and test a user-led resource for newly diagnosed patients with SPMS. Here, we describe the developmental phase, consisting of a literature review and a new research study involving key stakeholders, in which we construct the resource. Methods and analysis Round 1: The literature review and study will be conducted in parallel. The latter will identify patient needs using a qualitative approach consisting of: personal semistructured interviews with >15 recently diagnosed patients with SPMS; three focus group meetings (one with significant others of patients, one with neurologists and one with other health professionals caring for patients with SPMS). An online survey (>200 recently diagnosed Italian patients with SPMS) will follow to verify needs in a larger independent sample. An expert panel will outline a set of candidate resources/interventions that aim to satisfy the needs thus identified. Round 2: Consensus on the final resource will be obtained in a 1-day meeting of recently diagnosed patients with SPMS, significant others, health professionals and other stakeholders, using the nominal group technique. The expert panel will refine the resource, identify the outcome measures to assess its efficacy and ascertain the most suitable comparator (ManTra Phase 2, not part of this protocol). Ethics and dissemination The study protocol was approved by the ethics committees of each of the involved centres: Foundation IRCCS Neurological Institute C Besta, Milan; G D’Annunzio University of Chieti-Pescara and the Aldo Moro University of Bari. The results will be published in peer-reviewed journals, presented at conferences and a lay summary sent to participants. PMID:28838904

Employment among patients with multiple sclerosis-a population study.

PubMed

Bøe Lunde, Hanne Marie; Telstad, Wenche; Grytten, Nina; Kyte, Lars; Aarseth, Jan; Myhr, Kjell-Morten; Bø, Lars

2014-01-01

To investigate demographic and clinical factors associated with employment in MS. The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS. Logistic regression analysis was used to identify factors independently associated with current employment. After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed. Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

PubMed

Zivadinov, Robert; Ramasamy, Deepa P; Vaneckova, Manuela; Gandhi, Sirin; Chandra, Avinash; Hagemeier, Jesper; Bergsland, Niels; Polak, Paul; Benedict, Ralph Hb; Hojnacki, David; Weinstock-Guttman, Bianca

2017-09-01

Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.

The cost-effectiveness of disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis.

PubMed

Bozkaya, Duygu; Livingston, Terrie; Migliaccio-Walle, Kristen; Odom, Tanner

2017-03-01

The safety and efficacy of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has been established; however, it is not clear which provides optimal value, given benefit-risk profiles and costs. To compare the cost-effectiveness of current DMTs for patients with RRMS in the US. A Markov model predicting RRMS course following initiation of a DMT was created comparing outcomes (e.g. relapses, disease progression) and costs of natalizumab (NTZ), dimethyl fumarate (DMF), and peginterferon beta-1a (PEG) with fingolimod (FIN), glatiramer acetate (GA, 20 mg daily), and subcutaneous interferon beta-1a (IFN, 44 mcg), respectively, over 10 years. RRMS and secondary-progressive MS (SPMS) EDSS state transitions were predicted in 3-month cycles in which patients were at risk of death, relapse, or discontinuation. Upon DMT discontinuation, natural history progression and relapse rates were applied. Incremental cost-effectiveness ratios (ICERs) were estimated for the cost per relapse avoided, relapse-free years gained, progression avoided, and progression-free years gained. The impact of model parameters on outcomes was evaluated via one-way sensitivity analyses. Costs ranged from $561,177 (NTZ) to $616,251 (GA). NTZ, DMF, and PEG were dominant (less costly and more effective) compared to FIN, GA, and IFN, respectively, for all ICERs. Variability in drug costs and parameters that affected drug cost accrual (e.g. discontinuation rates and the decision to drop out after SPMS conversion) had a considerable impact on ICERs. Several simplifying assumptions were made that may represent potential limitations of this analysis (e.g. a constant treatment effect over time was assumed). The results from this analysis suggest that the NTZ, DMF, and PEG are cost-effective DMT choices compared to FIN, GA, and IFN, respectively. The actual impact on a particular plan will vary based on drug pricing and other factors affecting drug cost accrual.

Employment among Patients with Multiple Sclerosis-A Population Study

PubMed Central

Bøe Lunde, Hanne Marie; Telstad, Wenche; Grytten, Nina; Kyte, Lars; Aarseth, Jan; Myhr, Kjell-Morten; Bø, Lars

2014-01-01

Objective To investigate demographic and clinical factors associated with employment in MS. Methods The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS. Logistic regression analysis was used to identify factors independently associated with current employment. Results After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing –remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed. Conclusions Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual ’s needs in order to improve working ability among MS patients. PMID:25054972

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study.

PubMed

Marshall, Ian; Thrippleton, Michael J; Bastin, Mark E; Mollison, Daisy; Dickie, David A; Chappell, Francesca M; Semple, Scott I K; Cooper, Annette; Pavitt, Sue; Giovannoni, Gavin; Wheeler-Kingshott, Claudia A M Gandini; Solanky, Bhavana S; Weir, Christopher J; Stallard, Nigel; Hawkins, Clive; Sharrack, Basil; Chataway, Jeremy; Connick, Peter; Chandran, Siddharthan

2018-05-30

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of 'chronic' lesions in SPMS, and may represent a target for repair therapies.

Immunopathological Patterns from EAE and Theiler’s Virus Infection: Is Multiple Sclerosis a Homogenous 1-stage or Heterogenous 2-stage Disease?

PubMed Central

Martinez, Nicholas E.; Sato, Fumitaka; Omura, Seiichi; Minagar, Alireza; Alexander, J. Steven; Tsunoda, Ikuo

2012-01-01

Multiple sclerosis (MS) is a disease which can present in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose ‘1-stage’ and ‘2-stage’ disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the ‘1-stage disease’ theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The ‘2-stage disease’ theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler’s virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage. PMID:22633747

Subcutaneous interferon β-1a three times weekly and the natural evolution of gadolinium-enhancing lesions into chronic black holes in relapsing and progressive multiple sclerosis: Analysis of PRISMS and SPECTRIMS trials.

PubMed

Traboulsee, A; Li, Dkb; Tam, R; Zhao, G; Riddehough, A; Fang, J; Dangond, F; Kappos, L

2017-01-01

Evolution of gadolinium-enhancing lesions into chronic black holes (CBH) may be reduced by interferon (IFN) therapy. The objective of this paper is to assess the effect of IFN β-1a and placebo on CBH evolution and disability in patients with relapsing-remitting multiple sclerosis (RRMS), as well as CBH evolution in patients with secondary progressive multiple sclerosis (SPMS). A post hoc, exploratory analysis of patients with RRMS and SPMS with monthly MRI scans (months -1 to 9) from two separate placebo-controlled clinical trials of IFN β-1a was conducted. In RRMS patients, the risk of ≥1 evolved CBH was lower for IFN β-1a versus placebo (odds ratio 0.42; p  = 0.024); volume of newly evolved CBH was numerically reduced. A numerically higher proportion of patients with ≥1 evolving CBH vs no evolving CBH had confirmed three-month disability progression (four-year rate 55.8% vs 43.1%, respectively). Proportion of lesions evolving into CBH (patient level: 34.7% vs 12.6%, p  < 0.0001; lesion level: 28.8% vs 11.0%, p  < 0.0001) and evolved CBH volume (median 33.5 mm 3 (Quartile 1, 0.0; Quartile 3, 173.4) vs 0.0 mm 3 (0.0; 52.4); p  = 0.0008) was higher for SPMS than RRMS patients treated with IFN β-1a. In RRMS, IFN β-1a significantly decreased the proportion of new T1 Gd+ lesions evolving into CBH and the risk of developing a CBH. In patients with SPMS, more lesions develop to CBH, indicating reduced repair capacity, and the natural history of lesion development appears to be unaffected by IFN β-1a treatment.

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.

PubMed

Kappos, Ludwig; Bar-Or, Amit; Cree, Bruce A C; Fox, Robert J; Giovannoni, Gavin; Gold, Ralf; Vermersch, Patrick; Arnold, Douglas L; Arnould, Sophie; Scherz, Tatiana; Wolf, Christian; Wallström, Erik; Dahlke, Frank

2018-03-31

No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Novartis Pharma AG. Copyright © 2018 Elsevier Ltd. All rights reserved.

Human milk proresolving mediators stimulate resolution of acute inflammation.

PubMed

Arnardottir, Hildur; Orr, Sarah K; Dalli, Jesmond; Serhan, Charles N

2016-05-01

Human milk contains nutrients and bioactive products relevant to infant development and immunological protection. Here, we investigated the proresolving properties of milk using human milk lipid mediator isolates (HLMIs) and determined their impact on resolution programs in vivo and with human macrophages. HLMIs reduced the maximum neutrophil numbers (14.6±1.2 × 10(6)-11.0±1.0 × 10(6) cells per exudate) and shortened the resolution interval (Ri; 50% neutrophil reduction) by 54% compared with peritonitis. Using rigorous liquid-chromatography tandem-mass spectrometry (LC-MS-MS)-based lipid mediator (LM) metabololipidomics, we demonstrated that human milk possesses a proresolving LM-specialized proresolving mediator (LM-SPM) signature profile, containing SPMs (e.g. resolvins (Rv), protectins (PDs), maresins (MaRs), and lipoxins (LXs)) at bioactive levels (pico-nanomolar concentrations) that enhanced human macrophage efferocytosis and bacterial containment. SPMs identified in human milk included D-series Rvs (e.g., RvD1, RvD2, RvD3, AT-RvD3, and RvD4), PD1, MaR1, E-series Rvs (e.g. RvE1, RvE2, and RvE3), and LXs (LXA4 and LXB4). Of the SPMs identified in human milk, RvD2 and MaR1 (50 ng per mouse) individually shortened Ri by ∼75%. Milk from mastitis gave higher leukotriene B4 and prostanoids and lower SPM levels. Taken together, these findings provide evidence that human milk has proresolving actions via comprehensive LM-SPM profiling, describing a potentially novel mechanism in maternal-infant biochemical imprinting.

Association study of four polymorphisms in the interleukin-7 receptor alpha gene with multiple sclerosis in Eastern Iran.

PubMed

Haj, Mehrdad Sadeghi; Nikravesh, Abbas; Kakhki, Majid Pahlevan; Rakhshi, Nahid

2015-06-01

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) with unknown etiology. Various genetics and environmental factors contribute to the pathogenesis of the disease. The interleukin-7 receptor alpha chain (IL-7Ra) was identified as the first non-major histocompatibility complex (non-MHC) MS susceptibility locus. In this study we are trying to find the association of IL-7Ra gene polymorphisms with MS susceptibility in Eastern Iran. A case-control study was performed in two provinces Sistan & Baluchistan and Khorasan with 219 patients and 258 unrelated matched healthy controls, using PCR-RFLP method for four single nucleotide polymorphisms (SNPs) rs7718919, rs11567685, rs11567686 and rs6897932 of IL-7Ra gene. We found a tendency toward association with genotyping analyses in SNP rs7718919 (P=0.048, OR=4.344, and 95% CI=0.892-21.146); also genotype and allele frequency in gender and MS subtype stratification were shown to have significant association with MS. Analysis of two provinces separately showed a significant difference in results of the allele and genotype frequencies. Moreover, haplotyping analysis showed that (GTGC) has an association only in the male secondary-progressive multiple sclerosis (SPMS) patients in comparison to the healthy controls (P=0.043, OR=0.413, and 95% CI=0.179-0.955). IL7-Ra could be a susceptible gene to MS within the Eastern Iran population especially after MS and gender stratification.

Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis.

PubMed

D'Ambrosio, Alessandro; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo; Rocca, Maria A

2017-08-01

To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.

[Epidemiological aspects of multiple sclerosis in Lublin (Poland)].

PubMed

Łobińska, Alicja; Stelmasiak, Zbigniew

2004-01-01

The objective of this paper was to present an epidemiological analysis of multiple sclerosis (MS) in Lublin, identify MS prevalence as well as characterize the population of MS patients. Information about the patients was gathered and they were examined from 1996 to the end of 2000, that is within a 5-year period. The patients' data were obtained from the neurological departments in Lublin, most often neurological (but also general and ophthalmic) clinics, as well as from the Lublin MS Society. The remaining patients' data were obtained from the doctors, family members, the Lublin MS Society members, as well as from the hospital and clinic files. The patients were interviewed in detail using a prepared questionnaire. The diagnosis and its degree of certainty were determined in accordance with the Poser's criteria. The control group included 111 healthy people who were Lublin residents on the day of examination. The obtained results were analyzed in epidemiological and statistical terms. On the prevalence day (31 December 1997) there were 204 MS cases in Lublin, including 141 women (69%) and 63 men (31%). The calculated incidence ratio was 57.3/105. The average age of MS onset was estimated to be 30.1 years. On 31 December 1997 the average duration of the illness was 15.4 years. The average age for the examined cases was 45.5 years. The average DSS (Disability Status Scale) score was 3.5. Most often the disease began with a single symptom, in 155 cases (75.9%), whereas several symptoms occurred in 37 patients (18.1%). The most common symptoms at the illness onset were sensory impairments (52 patients), optic neuritis (42 people) and pyramidal symptoms (34 patients). The most common form of the illness was a disseminated form, which was diagnosed in 131 patients (64.2%). In the examined patient population four types of MS were recognized. The relapsing-remitting MS (RR-MS) was observed in 62 patients (30.3%), the secondary progressive MS (SP-MS) in 83 patients (40.6%), and the primary progressive MS (PP-MS) was characteristic of 40 people (19.6%), while 19 patients (9.3%) experienced a benign course of MS. Our results are typical for the region of high incidence of MS. They are similar to the data achieved in other populations of that region.

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner

PubMed Central

Kinoshita, Makoto; Sumi-Akamaru, Hisae; Sasaki, Tsutomu; Takata, Kazushiro; Koda, Toru; Namba, Akiko; Yamashita, Kazuya; Sanda, Eri; Sakaguchi, Manabu; Kumanogoh, Atsushi; Shirakura, Takashi; Tamura, Mizuho; Sakoda, Saburo; Mochizuki, Hideki

2017-01-01

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS. PMID:29107957

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner.

PubMed

Honorat, Josephe A; Nakatsuji, Yuji; Shimizu, Mikito; Kinoshita, Makoto; Sumi-Akamaru, Hisae; Sasaki, Tsutomu; Takata, Kazushiro; Koda, Toru; Namba, Akiko; Yamashita, Kazuya; Sanda, Eri; Sakaguchi, Manabu; Kumanogoh, Atsushi; Shirakura, Takashi; Tamura, Mizuho; Sakoda, Saburo; Mochizuki, Hideki; Okuno, Tatsusada

2017-01-01

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.

A new morphological approach for removing acid dye from leather waste water: preparation and characterization of metal-chelated spherical particulated membranes (SPMs).

PubMed

Şenay, Raziye Hilal; Gökalp, Safiye Meriç; Türker, Evren; Feyzioğlu, Esra; Aslan, Ahmet; Akgöl, Sinan

2015-03-15

In this study, p(HEMA-GMA) poly(hydroxyethyl methacrylate-co-glycidyl methacrylate) spherical particulated membranes (SPMs) were produced by UV-photopolymerization and the synthesized SPMs were coupled with iminodiacetic acid (IDA). Finally the novel SPMs were chelated with Cr(III) ions as ligand and used for removing acid black 210 dye. Characterizations of the metal-chelated SPMs were made by SEM, FTIR and swelling test. The water absorption capacities and acid dye adsorption properties of the SPMs were investigated and the results were 245.0, 50.0, 55.0 and 51.9% for p(HEMA), p(HEMA-GMA), p(HEMA-GMA)-IDA and p(HEMA-GMA)-IDA-Cr(III) SPMs respectively. Adsorption properties of the p(HEMA-GMA)-IDA-Cr(III) SPMs were investigated under different conditions such as different initial dye concentrations and pH. The optimum pH was observed at 4.3 and the maximum adsorption capacity was determined as 885.14 mg/g at about 8000 ppm initial dye concentration. The concentrations of the dyes were determined using a UV/Vis Spectrophotometer at a wavelength of 435 nm. Reusability of p(HEMA-GMA)-IDA-Cr(III) SPMs was also shown for five adsorption-desorption cycles without considerable decrease in its adsorption capacity. Finally, the results showed that the metal-chelated p(HEMA-GMA)-IDA SPMs were effective sorbent systems removing acid dye from leather waste water. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report.

PubMed

Berkovich, Regina

2017-10-01

To evaluate clinical and MRI outcomes after stopping or switching disease-modifying therapy in patients with stable MS. A retrospective chart review was conducted of stable MS patients who discontinued or switched their DMT from 2011 to 2015. Clinical and MRI outcomes were obtained at baseline and 1-year follow-up. For the DMT discontinuation group, 15 patients were included, with 67% female, 53% Caucasian, mean age of 45.3 ± 12.2 years, disease duration of 9.1 ± 4.3 years, MS type (80% RRMS, 20% SPMS), and EDSS of 3.7 ± 1.6. The average duration of stable MS course was 5.5 ± 3.7 years. Within a mean of 6.4 ± 2.2 months after DMT discontinuation, all 15 patients experienced worsening of MS disease. After re-evaluation of MS treatment options, all 15 patients were restarted on DMT, of which, 6 (40%) restarted on their prior DMT, 4 (26.7%) switched to another DMT due to adverse events on prior DMT, and 5 (33.3%) switched to a more potent DMT due to worsening of MS activity. One year follow-up showed 2 patients (13.3%) who were restarted on their prior DMT experienced a relapse and the remaining 13 patients (86.7%) had no clinical or MRI activities. For the DMT switch group, 23 patients were included, with 65% female, 61% Caucasian, a mean age of 46.9 ± 11.6 years, disease duration of 11.7 ± 5.1 years, MS Type (83% RRMS, 17% SPMS), and EDSS of 3.5 ± 0.9. After switching DMT, 9 (39.1%) patients experienced worsening of clinical or MRI outcomes at the 1-year follow-up. Of the 9 switch failures, the majority (N = 6) were due to switching to dimethyl fumarate. DMT discontinuation in stable MS patients resulted in worsening of MS disease course for all patients, which improved upon DMT restart or switch. In contrast, 39% of MS stable patients experienced worsening of MS disease course when switched to another DMT, with DMT selection potentially impacting switch outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Genomic organization of plant aminopropyl transferases.

PubMed

Rodríguez-Kessler, Margarita; Delgado-Sánchez, Pablo; Rodríguez-Kessler, Gabriela Theresia; Moriguchi, Takaya; Jiménez-Bremont, Juan Francisco

2010-07-01

Aminopropyl transferases like spermidine synthase (SPDS; EC 2.5.1.16), spermine synthase and thermospermine synthase (SPMS, tSPMS; EC 2.5.1.22) belong to a class of widely distributed enzymes that use decarboxylated S-adenosylmethionine as an aminopropyl donor and putrescine or spermidine as an amino acceptor to form in that order spermidine, spermine or thermospermine. We describe the analysis of plant genomic sequences encoding SPDS, SPMS, tSPMS and PMT (putrescine N-methyltransferase; EC 2.1.1.53). Genome organization (including exon size, gain and loss, as well as intron number, size, loss, retention, placement and phase, and the presence of transposons) of plant aminopropyl transferase genes were compared between the genomic sequences of SPDS, SPMS and tSPMS from Zea mays, Oryza sativa, Malus x domestica, Populus trichocarpa, Arabidopsis thaliana and Physcomitrella patens. In addition, the genomic organization of plant PMT genes, proposed to be derived from SPDS during the evolution of alkaloid metabolism, is illustrated. Herein, a particular conservation and arrangement of exon and intron sequences between plant SPDS, SPMS and PMT genes that clearly differs with that of ACL5 genes, is shown. The possible acquisition of the plant SPMS exon II and, in particular exon XI in the monocot SPMS genes, is a remarkable feature that allows their differentiation from SPDS genes. In accordance with our in silico analysis, functional complementation experiments of the maize ZmSPMS1 enzyme (previously considered to be SPDS) in yeast demonstrated its spermine synthase activity. Another significant aspect is the conservation of intron sequences among SPDS and PMT paralogs. In addition the existence of microsynteny among some SPDS paralogs, especially in P. trichocarpa and A. thaliana, supports duplication events of plant SPDS genes. Based in our analysis, we hypothesize that SPMS genes appeared with the divergence of vascular plants by a processes of gene duplication and the acquisition of unique exons of as-yet unknown origin. 2010 Elsevier Masson SAS. All rights reserved.

Cost-utility of First-line Disease-modifying Treatments for Relapsing-Remitting Multiple Sclerosis.

PubMed

Soini, Erkki; Joutseno, Jaana; Sumelahti, Marja-Liisa

2017-03-01

This study evaluated the cost-effectiveness of first-line treatments of relapsing-remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily, interferon [IFN]-β1a 44 µg TIW, IFN-β1b 250 µg EOD, and IFN-β1a 30 µg IM QW) and best supportive care (BSC) in the health care payer setting in Finland. The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained, 3%/y discounting). Markov cohort modeling with a 15-year time horizon was employed. During each 1-year modeling cycle, patients either maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS) or showed EDSS progression in SPMS, experienced relapse with/without hospitalization, experienced an adverse event (AE), or died. Patients׳ characteristics, RRMS progression probabilities, and standardized mortality ratios were derived from a registry of patients with MS in Finland. A mixed-treatment comparison (MTC) informed the treatment effects. Finnish EuroQol Five-Dimensional Questionnaire, Three-Level Version quality-of-life and direct-cost estimates associated with EDSS scores, relapses, and AEs were applied. Four approaches were used to assess the outcomes: cost-effectiveness plane and efficiency frontiers (relative value of efficient treatments); cost-effectiveness acceptability frontier, which demonstrated optimal treatment to maximize net benefit; Bayesian treatment ranking (BTR); and an impact investment assessment (IIA; a cost-benefit assessment), which increased the clinical interpretation and appeal of modeled outcomes in terms of absolute benefit gained with fixed drug-related budget. Robustness of results was tested extensively with sensitivity analyses. Based on the modeled results, teriflunomide was less costly, with greater QALYs, versus glatiramer acetate and the IFNs. Teriflunomide had the lowest ICER (24,081) versus BSC. DMF brought marginally more QALYs (0.089) than did teriflunomide, with greater costs over the 15 years. The ICER for DMF versus teriflunomide was 75,431. Teriflunomide had >50% cost-effectiveness probabilities with a willingness-to-pay threshold of <€77,416/QALY gained. According to BTR, teriflunomide was first-best among the disease-modifying therapies, with potential willingness-to-pay thresholds of up to €68,000/QALY gained. In the IIA, teriflunomide was associated with the longest incremental quality-adjusted survival and time without cane use. Generally, primary outcomes results were robust, based on the sensitivity analyses. The results were sensitive only to large changes in analysis perspective or mixed-treatment comparison. The results were sensitive only to large changes in analysis perspective or MTC. Based on the analyses, teriflunomide was cost-effective versus BSC or DMF with the common threshold values, was dominant versus other first-line RRMS treatments, and provided the greatest impact on investment. Teriflunomide is potentially the most cost-effective option among first-line treatments of RRMS in Finland. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

[The efficacy of the exoskeleton ExoAtlet to restore walking in patients with multiple sclerosis].

PubMed

Kotov, S V; Lijdvoy, V Yu; Sekirin, A B; Petrushanskaya, K A; Pismennaya, E V

2017-01-01

To investigate the efficacy and safety of the exoskeleton ExoAtlet in complex therapy of patients with multiple sclerosis (MS). A pilot study within the prospective open controlled program was conducted. Eighteen patients with relapsing-remitting MS (RRMS) in remission and secondary progressive MS (SPMS) with the level of neurological deficit on the EDSS from 3 to 7 points have completed the study. EDSS, MSFC, HADS, MoCA scales were administered and the force measuring insoles F-Scan Tekscan (USA) were used to study the biomechanics of walking. Good tolerability of workload within 30-40 min. was observed. The improvement in the EDSS was detected in 9 patients, in whole, a significant positive trend (p<0.01) was shown. The study of the biomechanics of the walk showed its significant impairment compared to healthy individuals: reduction of parameters of rate, speed and step length, significant instability, pronounced asymmetry, the decrease in support and shock lower limb function, high coefficient of variability of the parameters, the phenomenon of recurrence of the vertical component of support reactions. After a course of exercise of walking in the exoskeleton, the walking speed and stability increased, oscillation of the body decreased, support function increased, the phenomenon of cyclical changes of the vertical component of support reactions reduced. The results of the pilot study showed promising future research opportunities for robotic-assisted walking and maintenance of the vertical posture with the help of the exoskeleton ExoAtlet to restore the abilities of movement in MS patients with locomotor disorders.

Second primary malignancies in chronic myeloid leukemia.

PubMed

Shah, Binay Kumar; Ghimire, Krishna Bilas

2014-12-01

Survival of patients with chronic myeloid leukemia (CML) has improved with the use of imatinib and other tyrosine kinase inhibitors. There is limited data on second primary malignancies (SPM) in CML. We analyzed the SPMs rates among CML patients reported to Surveillance, Epidemiology, and End Results (SEER) database during pre-(1992-2000) and post-(2002-2009) era. We used SEER Multiple Primary-Standardized Incidence Ratio session to calculate standardized incidence ratios (SIRs). Among 8,511 adult CML patients, 446 patients developed 473 SPMs. The SIR for SPMs in CML patients was significantly higher with observed/expected ratio:1.27, P < 0.05 and absolute excess risk of 32.09 per 10,000 person years compared to general population. The rate of SPMs for cancers of all sites in post-imatinib era were significantly higher compared to pre-imatinib era with observed/expected ratio of 1.48 versus 1.06, P = 0.03. This study showed that risk of SPMs is higher among CML patients. The risk of SPMs is significantly higher in post-imatinib era compared to pre-imatinib era.

Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long-term clinical data and switchable treatments

PubMed Central

2013-01-01

Background Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs). Methods A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model. Results ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913. Conclusions The Markov pharmacoeconomics model determined that according to suggested threshold for developing countries by world health organization, all brand INF β products are cost effective in Iran except Avonex. The best strategy among INF β therapies is CBP intramuscular INF β-1a (Cinnovex). Results showed that a policy of encouraging accessibility to CBPs and biosimilars could make even high technology products cost-effective in LMICs. PMID:23800250

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial.

PubMed

Sharafaddinzadeh, Naser; Moghtaderi, Ali; Kashipazha, Davood; Majdinasab, Nastaran; Shalbafan, Bita

2010-08-01

Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire. A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups. Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study. The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Paclitaxel-loaded iron platinum stealth immunomicelles are potent MRI imaging agents that prevent prostate cancer growth in a PSMA-dependent manner

PubMed Central

Taylor, Robert M; Sillerud, Laurel O

2012-01-01

Background and methods: Problems with the clinical management of prostate cancer include the lack of both specific detection and efficient therapeutic intervention. We report the encapsulation of superparamagnetic iron platinum nanoparticles (SIPPs) and paclitaxel in a mixture of polyethyleneglycolated, fluorescent, and biotin-functionalized phospholipids to create multifunctional SIPP-PTX micelles (SPMs) that were conjugated to an antibody against prostate-specific membrane antigen (PSMA) for the specific targeting, magnetic resonance imaging (MRI), and treatment of human prostate cancer xenografts in mice. Results: SPMs were 45.4 ± 24.9 nm in diameter and composed of 160.7 ± 22.9 μg/mL iron, 247.0 ± 33.4 μg/mL platinum, and 702.6 ± 206.0 μg/mL paclitaxel. Drug release measurements showed that, at 37°C, half of the paclitaxel was released in 30.2 hours in serum and two times faster in saline. Binding assays suggested that PSMA-targeted SPMs specifically bound to C4-2 human prostate cancer cells in vitro and released paclitaxel into the cells. In vitro, paclitaxel was 2.2 and 1.6 times more cytotoxic than SPMs to C4-2 cells at 24 and 48 hours of incubation, respectively. After 72 hours of incubation, paclitaxel and SPMs were equally cytotoxic. SPMs had MRI transverse relaxivities of 389 ± 15.5 Hz/mM iron, and SIPP micelles with and without drug caused MRI contrast enhancement in vivo. Conclusion: Only PSMA-targeted SPMs and paclitaxel significantly prevented growth of C4-2 prostate cancer xenografts in nude mice. Furthermore, mice injected with PSMA-targeted SPMs showed significantly more paclitaxel and platinum in tumors, compared with nontargeted SPM-injected and paclitaxel-injected mice. PMID:22915856

The roles of special proresolving mediators in pain relief.

PubMed

Zhang, Lan-Yu; Jia, Ming-Rui; Sun, Tao

2018-02-08

The resolution of acute inflammation, once thought to be a passive process, is now recognized as an active one. The productions of endogenous special proresolving mediators (SPMs) are involved in this process. SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated from ω-6 arachidonic acid or ω-3 poly-unsaturated fatty acids during the resolution phase of acute inflammation. They have potent anti-inflammatory and proresolving actions in various inflammatory disorders. Due to the potent proresolving and anti-inflammatory effects, SPMs are also used for pain relief. This review focuses on the mechanisms by which SPMs act on their respective G-protein-coupled receptors in immune cells and nerve cells to normalize pain via regulating inflammatory mediators, transient receptor potential ion channels, and central sensitization. SPMs may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation.

EGNOS Monitoring Prepared in Space Research Centre P.A.S. for SPMS Project

NASA Astrophysics Data System (ADS)

Swiatek, Anna; Jaworski, Leszek; Tomasik, Lukasz

2017-12-01

The European Geostationary Overlay Service (EGNOS) augments Global Positioning System (GPS) by providing correction data and integrity information for improving positioning over Europe. EGNOS Service Performance Monitoring Support (SPMS) project has assumed establishment, maintenance and implementation of an EGNOS performance monitoring network. The paper presents preliminary results of analyses prepared in Space Research Centre, Polish Academy of Sciences (Warsaw), as one of partners in SPMS project.

BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma.

PubMed

Rossi, Adriana; Mark, Tomer; Jayabalan, David; Christos, Paul; Zafar, Faiza; Pekle, Karen; Pearse, Roger; Chen-Kiang, Selina; Coleman, Morton; Niesvizky, Ruben

2013-03-14

The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.

BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma

PubMed Central

Rossi, Adriana; Mark, Tomer; Jayabalan, David; Christos, Paul; Zafar, Faiza; Pekle, Karen; Pearse, Roger; Chen-Kiang, Selina; Coleman, Morton

2013-01-01

The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203. PMID:23299315

Incidence of Second Primary Malignancies Following Colorectal Cancer: A Distinct Pattern of Occurrence Between Colon and Rectal Cancers and Association of Co-Morbidity with Second Primary Malignancies in a Population-Based Cohort of 98,876 Patients in Taiwan

PubMed Central

Lee, Yu-Ting; Liu, Chia-Jen; Hu, Yu-Wen; Teng, Chung-Jen; Tzeng, Cheng-Hwai; Yeh, Chiu-Mei; Chen, Tzeng-Ji; Lin, Jen-Kou; Lin, Chun-Chi; Lan, Yuan-Tzu; Wang, Huann-Sheng; Yang, Shung-Haur; Jiang, Jeng-Kai; Chen, Wei-Shone; Lin, Tzu-Chen; Chang, Shih-Ching; Chen, Ming-Huang; Teng, Hao-Wei; Liu, Jin-Hwang; Yen, Chueh-Chuan

2015-01-01

Abstract The purpose of this study is to determine the features of second primary malignancies (SPMs) among patients with prior colorectal cancer (CRC) using a nationwide population-based dataset. Patients with CRC newly diagnosed between 1996 and 2011, and >1 year of follow-up were recruited from the Taiwan National Health Insurance database. Standardized incidence ratios (SIRs) of SPMs in patients with CRC were calculated. During the 16-year study period, 4259 SPMs developed among 98,876 CRC patients. The median duration of follow-up was 4.03 years. The SIR for all SPMs was 1.13 (95% confidence interval = 1.10–1.17). Compared with the general population, a higher incidence of thyroid, prostate, ovarian, and hematologic malignancies developed among patients with colon cancer, whereas the risk for bone and soft tissue cancers increased among patients with rectal cancer. The risk for breast, bladder, kidney, lung, and uterine cancers was significantly higher in patients with colon and rectal cancers than the general population. The risk for liver and biliary tract cancers declined in patients with rectal cancer. Based on multivariate analysis among patients with CRC, age ≥70 years, men, chronic obstructive pulmonary disease (COPD), cirrhosis, and dyslipidemia were independent predictors of an SPM. In conclusion, patients with CRC were at increased risk for a second cancer. The pattern of SPMs was distinct between patients with colon and rectal cancer. Age, men, COPD, cirrhosis, and dyslipidemia were independent risk factors for SPMs. Surveillance and education should be provided for survivors with respect to risk for SPMs. PMID:26131831

Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis.

PubMed

Agah, Elmira; Zardoui, Arshia; Saghazadeh, Amene; Ahmadi, Mona; Tafakhori, Abbas; Rezaei, Nima

2018-01-01

Identifying a reliable biomarker may accelerate diagnosis of multiple sclerosis (MS) and lead to early management of the disease. Accumulating evidence suggest that cerebrospinal fluid (CSF) and peripheral blood concentration of osteopontin (OPN) may have diagnostic and prognostic value in MS. We conducted a systematic review and meta-analysis of studies that measured peripheral blood and CSF levels of OPN in MS patients and controls to evaluate the diagnostic potential of this biomarker better. We searched PubMed, Web of Science and Scopus databases to find articles that measured OPN concentration in peripheral blood and CSF samples from MS patients up to October 19, 2016. Q statistic tests and the I2 index were applied for heterogeneity assessment. If the I2 index was less than 40%, the fixed-effects model was used for meta-analysis. Random-effects meta-analysis was chosen if the I2 value was greater than 40%. After removal of duplicates, 918 articles were identified, and 27 of them fulfilled the inclusion criteria. We included 22 eligible studies in the final meta-analysis. MS patients, in general, had considerably higher levels of OPN in their CSF and blood when compared to all types of controls (p<0.05). When the comparisons were made between different subtypes of MS patients and controls, the results pointed to significantly higher levels of OPN in CSF of MS subgroups (p<0.05). All subtypes of MS patients, except CIS patients, had increased blood levels of OPN compared to controls (p<0.05). In the second set of meta-analyses, we compared the peripheral blood and CSF concentrations of OPN between MS patient subtypes. CIS patients had significantly lower levels of OPN both in their peripheral blood and CSF compared to patients with progressive subtypes of MS (p<0.05). CSF concentration of OPN was significantly higher among RRMS patients compared to the CIS patients and SPMS patients (P<0.05). Finally, patients with active MS had significantly higher OPN levels in their CSF compared to patients with stable disease (P = 0.007). The result of this study confirms that increased levels of OPN exist in CSF and peripheral blood of MS patients and strengthens the evidence regarding the clinical utility of OPN as a promising and validated biomarker for MS.

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

PubMed Central

Mainero, C; Benner, T; Radding, A; van der Kouwe, A; Jensen, R; Rosen, B R.; Kinkel, R P.

2009-01-01

Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods: We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 × 033 × 1 mm3), and a 3-dimensional magnetization-prepared rapid gradient echo. Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing–remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test). Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. GLOSSARY ANOVA = analysis of variance; BN = background noise; CNR = contrast-to-noise ratio; DIR = double-inversion recovery; EDSS = Expanded Disability Status Scale; FLAIR = fluid-attenuated inversion recovery; FLASH = fast low-angle shot; GM = gray matter; MPRAGE = magnetization-prepared rapid gradient echo; MR = magnetic resonance; MS = multiple sclerosis; NACGM = normal-appearing cortical gray matter; RF = radiofrequency; ROI = region of interest; RRMS = relapsing–remitting multiple sclerosis; SNR = signal-to-noise ratio; SPMS = secondary progressive multiple sclerosis; TA = time of acquisition; TE = echo time; TR = repetition time; TSE = turbo spin-echo; WM = white matter. PMID:19641168

The impact of missing sensor information on surgical workflow management.

PubMed

Liebmann, Philipp; Meixensberger, Jürgen; Wiedemann, Peter; Neumuth, Thomas

2013-09-01

Sensor systems in the operating room may encounter intermittent data losses that reduce the performance of surgical workflow management systems (SWFMS). Sensor data loss could impact SWFMS-based decision support, device parameterization, and information presentation. The purpose of this study was to understand the robustness of surgical process models when sensor information is partially missing. SWFMS changes caused by wrong or no data from the sensor system which tracks the progress of a surgical intervention were tested. The individual surgical process models (iSPMs) from 100 different cataract procedures of 3 ophthalmologic surgeons were used to select a randomized subset and create a generalized surgical process model (gSPM). A disjoint subset was selected from the iSPMs and used to simulate the surgical process against the gSPM. The loss of sensor data was simulated by removing some information from one task in the iSPM. The effect of missing sensor data was measured using several metrics: (a) successful relocation of the path in the gSPM, (b) the number of steps to find the converging point, and (c) the perspective with the highest occurrence of unsuccessful path findings. A gSPM built using 30% of the iSPMs successfully found the correct path in 90% of the cases. The most critical sensor data were the information regarding the instrument used by the surgeon. We found that use of a gSPM to provide input data for a SWFMS is robust and can be accurate despite missing sensor data. A surgical workflow management system can provide the surgeon with workflow guidance in the OR for most cases. Sensor systems for surgical process tracking can be evaluated based on the stability and accuracy of functional and spatial operative results.

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

PubMed

Fernández, Oscar; Izquierdo, Guillermo; Fernández, Victoria; Leyva, Laura; Reyes, Virginia; Guerrero, Miguel; León, Antonio; Arnaiz, Carlos; Navarro, Guillermo; Páramo, Maria Dolores; Cuesta, Antonio De la; Soria, Bernat; Hmadcha, Abdelkrim; Pozo, David; Fernandez-Montesinos, Rafael; Leal, Maria; Ochotorena, Itziar; Gálvez, Patricia; Geniz, Maria Angeles; Barón, Francisco Javier; Mata, Rosario; Medina, Cristina; Caparrós-Escudero, Carlos; Cardesa, Ana; Cuende, Natividad

2018-01-01

Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

Gas Phase Chemistry and Molecular Complexity: How Far Do They Go?

NASA Astrophysics Data System (ADS)

Balucani, Nadia

2016-07-01

The accumulation of organic molecules of increasing complexity is believed to be an important step toward the emergence of life. But how massive organic synthesis could occur in primitive Earth, i.e. a water-dominated environment, is a matter of debate. Two alternative theories have been suggested so far: endogenous and exogenous synthesis. In the first theory, the synthesis of simple organic molecules having a strong prebiotic potential (simple prebiotic molecules SPMs, such as H2CO, HCN, HC3N, NH2CHO) occurred directly on our planet starting from simple parent molecules of the atmosphere, liquid water and various energy sources. Miller's experiment was a milestone in this theory, but it was later recognized that the complexity of a planet cannot be reproduced in a single laboratory experiment. Some SPMs have been identified in the N2-dominated atmosphere of Titan (a massive moon of Saturn), which is believed to be reminiscent of the primitive terrestrial atmosphere. As such, the atmosphere of Titan represents a planetary scale laboratory for the comprehension of SPM formation in an environment close enough to primitive Earth and is the current frontier in the endogenous theory exploration. In the exogenous theory, SPMs came from space, the carriers being comets, asteroids and meteorites. The rationale behind this suggestion is that plenty of SPMs have been observed in interstellar clouds (ISCs), including star-forming regions, and in small bodies like comets, asteroids and meteorites. Therefore, the basic idea is that SPMs were formed in the solar nebula, preserved during the early phases of the Solar System formation in the body of comets/asteroids/meteorites and finally delivered to Earth by cometary and meteoritic falls. In this contribution, the status of our knowledge on how SPMs can be formed in the gas phase, either in the primitive terrestrial atmosphere or in the cold nebula from which the Solar System originated, will be presented. Particular attention will be given to neutral-neutral reactions.

MRI Analysis of White Matter Myelin Water Content in Multiple Sclerosis: A Novel Approach Applied to Finding Correlates of Cortical Thinning

PubMed Central

Dayan, Michael; Hurtado Rúa, Sandra M.; Monohan, Elizabeth; Fujimoto, Kyoko; Pandya, Sneha; LoCastro, Eve M.; Vartanian, Tim; Nguyen, Thanh D.; Raj, Ashish; Gauthier, Susan A.

2017-01-01

A novel lesion-mask free method based on a gamma mixture model was applied to myelin water fraction (MWF) maps to estimate the association between cortical thickness and myelin content, and how it differs between relapsing-remitting (RRMS) and secondary-progressive multiple sclerosis (SPMS) groups (135 and 23 patients, respectively). It was compared to an approach based on lesion masks. The gamma mixture distribution of whole brain, white matter (WM) MWF was characterized with three variables: the mode (most frequent value) m1 of the gamma component shown to relate to lesion, the mode m2 of the component shown to be associated with normal appearing (NA) WM, and the mixing ratio (λ) between the two distributions. The lesion-mask approach relied on the mean MWF within lesion and within NAWM. A multivariate regression analysis was carried out to find the best predictors of cortical thickness for each group and for each approach. The gamma-mixture method was shown to outperform the lesion-mask approach in terms of adjusted R2, both for the RRMS and SPMS groups. The predictors of the final gamma-mixture models were found to be m1 (β = 1.56, p < 0.005), λ (β = −0.30, p < 0.0005) and age (β = −0.0031, p < 0.005) for the RRMS group (adjusted R2 = 0.16), and m2 (β = 4.72, p < 0.0005) for the SPMS group (adjusted R2 = 0.45). Further, a DICE coefficient analysis demonstrated that the lesion mask had more overlap to an ROI associated with m1, than to an ROI associated with m2 (p < 0.00001), and vice versa for the NAWM mask (p < 0.00001). These results suggest that during the relapsing phase, focal WM damage is associated with cortical thinning, yet in SPMS patients, global WM deterioration has a much stronger influence on secondary degeneration. Through these findings, we demonstrate the potential contribution of myelin loss on neuronal degeneration at different disease stages and the usefulness of our statistical reduction technique which is not affected by the typical bias associated with approaches based on lesion masks. PMID:28603479

Specialized proresolving lipid mediators in humans with the metabolic syndrome after n-3 fatty acids and aspirin.

PubMed

Barden, Anne E; Mas, Emilie; Croft, Kevin D; Phillips, Michael; Mori, Trevor A

2015-12-01

The metabolic syndrome (MetS) is associated with a chronic low-grade inflammatory state and may be affected by the ability to resolve inflammation, which is an active process that involves specialized proresolving lipid mediators (SPMs) derived from n-3 (ω-3) fatty acids. We compared plasma concentrations of SPMs in men and women with features of the MetS and in healthy matched control subjects in response to intakes of n-3 fatty acids and aspirin. MetS volunteers (n = 22) and healthy, matched controls (n = 21) were studied in parallel for 4 wk. Both groups took n-3 fatty acids (2.4 g/d) for 4 wk with the addition of aspirin (300 mg/d) during the last 7 d. Blood was collected at baseline and at 3 and 4 wk. Plasma SPMs were measured with the use of liquid chromatography-tandem mass spectrometry and included 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins, 17-hydroxydocosahexaenoic acid (17-HDHA), D-series resolvins, 14-hydroxydocosahexaenoic acid (14-HDHA), and maresin-1. Baseline SPMs did not differ between groups. There was an increase in the SPM precursors 18-HEPE, 17-HDHA, and 14-HDHA after n-3 fatty acid supplementation that was significantly attenuated in the MetS (P < 0.05). However, the E-series resolvins increased to a similar extent in the groups after n-3 fatty acid supplementation, and the D-series resolvins were not different from those at baseline. The addition of aspirin to n-3 fatty acids did not alter any SPMs in either group. Volunteers with MetS had reduced plasma concentrations of the precursors of the E- and D- series resolvins as well as of 14-HDHA in response to n-3 fatty acid supplementation. However, plasma E-series resolvins were increased to a similar extent after n-3 fatty acid supplementation in both groups, and the addition of aspirin to n-3 fatty acid supplementation did not alter any of the plasma SPMs in MetS and control subjects. Additional studies in the MetS are required to determine whether SPMs affect the ability to mount an appropriate response to infection. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12610000708055. © 2015 American Society for Nutrition.

Epidemiological characteristics and functional disability of multiple sclerosis patients in Kosovo.

PubMed

Zeqiraj, Kamber; Kruja, Jera; Kabashi, Serbeze; Muçaj, Sefedin

2014-01-01

Multiple Sclerosis (MS) is a chronic recurrent neurological disease that affects the Central Nervous System. This study aims to determine epidemiological factors that affect the appearance of MS, such as: incidence, prevalence, mortality, case appearance in accordance with the disease phase RRMS, SPMS, PPMS, gender, age, age group, and EDSS. Deals with analyzing diagnosed and treated patients in the Clinic of Neurology in Prishtina during the period of 2003-2012. The research was conducted through a questionnaire applied in the diagnosed cases of MS. Information on patients was gathered from: history of illness, discharge reports and other relevant documents on MS illness. Clinical and epidemiological-descriptive study methods were used. The acquired results are shown through tables, graphics. Statistical processing was conducted with Microsoft Office Excel. From the total number of doubtful hospitalized cases of demyelinization (644) in the Clinic of Neurology in Prishtina, 412 cases (64%) were diagnosed with MS. For the period of 2003-2012 the prevalence of MS has been 19.6 of patients in 100,000 inhabitants. MS incidence rate was 0.95 of patients in 100,000 inhabitants. MS mortality rate was 0.14 of deceased in 100,000 inhabitants. The ratio female--male is 2.3:1. A larger number of patients fall within the age group of 30-39 years-old. Clinical form trends: RRSM 72.3%, SPSM 22.6%, PPSM 5.1%. The rate of EDSS 78.3% (0-3.5), 14.9% (4-6.5), 6.8% (7-9).

Epidemiological characteristics and functional disability of multiple sclerosis patients in kosovo.

PubMed

Zeqiraj, Kamber; Kruja, Jera; Kabashi, Serbeze; Muçaj, Sefedin

2014-06-01

Multiple Sclerosis (MS) is a chronic recurrent neurological disease that affects the Central Nervous System. This study aims to determine epidemiological factors that affect the appearance of MS, such as: incidence, prevalence, mortality, case appearance in accordance with the disease phase RRMS, SPMS, PPMS, gender, age, age group, and EDSS. Deals with analyzing diagnosed and treated patients in the Clinic of Neurology in Prishtina during the period of 2003-2012. The research was conducted through a questionnaire applied in the diagnosed cases of MS. Information on patients was gathered from: history of illness, discharge reports and other relevant documents on MS illness. Clinical and epidemiological-descriptive study methods were used. The acquired results are shown through tables, graphics. Statistical processing was conducted with Microsoft Office Excel. From the total number of doubtful hospitalized cases of demyelinization (644) in the Clinic of Neurology in Prishtina, 412 cases (64%) were diagnosed with MS. For the period of 2003-2012 the prevalence of MS has been 19.6 of patients in 100,000 inhabitants. MS incidence rate was 0.95 of patients in 100,000 inhabitants. MS mortality rate was 0.14 of deceased in 100,000 inhabitants. The ratio female - male is 2.3:1. A larger number of patients fall within the age group of 30-39 years-old. Clinical form trends: RRSM 72.3%, SPSM 22.6%, PPSM 5.1%. The rate of EDSS 78.3% (0-3.5), 14.9% (4-6.5), 6.8% (7-9).

Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases.

PubMed

Krishnamoorthy, Nandini; Abdulnour, Raja-Elie E; Walker, Katherine H; Engstrom, Braden D; Levy, Bruce D

2018-07-01

Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

PubMed Central

Basil, Maria C.; Levy, Bruce D.

2017-01-01

Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation — that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection. PMID:26688348

FATES: a flexible analysis toolkit for the exploration of single-particle mass spectrometer data

NASA Astrophysics Data System (ADS)

Sultana, Camille M.; Cornwell, Gavin C.; Rodriguez, Paul; Prather, Kimberly A.

2017-04-01

Single-particle mass spectrometer (SPMS) analysis of aerosols has become increasingly popular since its invention in the 1990s. Today many iterations of commercial and lab-built SPMSs are in use worldwide. However, supporting analysis toolkits for these powerful instruments are outdated, have limited functionality, or are versions that are not available to the scientific community at large. In an effort to advance this field and allow better communication and collaboration between scientists, we have developed FATES (Flexible Analysis Toolkit for the Exploration of SPMS data), a MATLAB toolkit easily extensible to an array of SPMS designs and data formats. FATES was developed to minimize the computational demands of working with large data sets while still allowing easy maintenance, modification, and utilization by novice programmers. FATES permits scientists to explore, without constraint, complex SPMS data with simple scripts in a language popular for scientific numerical analysis. In addition FATES contains an array of data visualization graphic user interfaces (GUIs) which can aid both novice and expert users in calibration of raw data; exploration of the dependence of mass spectral characteristics on size, time, and peak intensity; and investigations of clustered data sets.

Epidemiological Characteristics and Functional Disability of Multiple Sclerosis Patients in Kosovo

PubMed Central

Zeqiraj, Kamber; Kruja, Jera; Kabashi, Serbeze; Muçaj, Sefedin

2014-01-01

Background and objectives: Multiple Sclerosis (MS) is a chronic recurrent neurological disease that affects the Central Nervous System. This study aims to determine epidemiological factors that affect the appearance of MS, such as: incidence, prevalence, mortality, case appearance in accordance with the disease phase RRMS, SPMS, PPMS, gender, age, age group, and EDSS. Materials and methods: Deals with analyzing diagnosed and treated patients in the Clinic of Neurology in Prishtina during the period of 2003-2012. The research was conducted through a questionnaire applied in the diagnosed cases of MS. Information on patients was gathered from: history of illness, discharge reports and other relevant documents on MS illness. Clinical and epidemiological-descriptive study methods were used. The acquired results are shown through tables, graphics. Statistical processing was conducted with Microsoft Office Excel. Results: From the total number of doubtful hospitalized cases of demyelinization (644) in the Clinic of Neurology in Prishtina, 412 cases (64%) were diagnosed with MS. For the period of 2003–2012 the prevalence of MS has been 19.6 of patients in 100,000 inhabitants. MS incidence rate was 0.95 of patients in 100,000 inhabitants. MS mortality rate was 0.14 of deceased in 100,000 inhabitants. The ratio female – male is 2.3:1. A larger number of patients fall within the age group of 30-39 years-old. Clinical form trends: RRSM 72.3%, SPSM 22.6%, PPSM 5.1%. The rate of EDSS 78.3% (0–3.5), 14.9% (4–6.5), 6.8% (7–9). PMID:25568528

Subsequent primary malignancies after diffuse large B-cell lymphoma in the modern treatment era.

PubMed

Tao, Li; Clarke, Christina A; Rosenberg, Aaron S; Advani, Ranjana H; Jonas, Brian A; Flowers, Christopher R; Keegan, Theresa H M

2017-07-01

With the addition of rituximab and other treatment advances, survival after diffuse large B-cell lymphoma (DLBCL) has improved, but subsequent primary malignancies (SPMs) have emerged as an important challenge for DLBCL survivorship. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23 879 patients who survived at least 1 year after a first primary DLBCL diagnosed during 1989-2012, compared to the general population in California. Cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. We found that the incidence of acute myeloid leukaemia (AML) nearly doubled in the post-rituximab era [SIR (95% CI) 4·39 (2·51-7·13) pre- (1989-2000) and 8·70 (6·62-11·22) post-rituximab (2001-2012)]. Subsequent thyroid cancer was rare pre-rituximab, but increased substantially after 2001 [0·66 (0·08-2·37) vs. 2·27(1·44-3·41)]. The 5-year CMI for all SPMs (4·77% pre- vs. 5·41% post-rituximab, P = 0·047), AML (0·15% vs. 0·41%, P = 0·003), thyroid cancer (0·03% vs. 0·15%, P = 0·003) and melanoma (0·25% vs. 0·42%, P = 0·020) were greater in DLBCL patients diagnosed in the post- versus pre-rituximab period. This study provides insight into the changing pattern of SPM occurrence after the introduction of rituximab, which may elucidate the aetiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients. © 2017 John Wiley & Sons Ltd.

Secondary Primary Malignancies in Multiple Myeloma: An Old Nemesis Revisited

PubMed Central

Yang, Jay; Terebelo, Howard R.; Zonder, Jeffrey A.

2012-01-01

The treatment of myeloma has undergone extraordinary improvements in the past half century. These advances have been accompanied by a concern for secondary primary malignancies (SPMs). It has been known for decades that extended therapy with alkylating chemotherapy agents, such as melphalan, carries an increased risk of therapy-related myelodysplastic syndrome and/or acute myeloid leukemia (t-MDS/AML), with a cumulative risk as high as 10–15%. High-dose chemotherapy with autologous stem cell support became widely accepted for myeloma in the 1990s. Despite the use of high doses of melphalan, the risk of t-MDS/AML with this procedure is estimated to be less than 5%, with much of this risk attributable to pretransplant therapy. Recently, lenalidomide has come under scrutiny for its possible association with SPMs. It is too soon to declare a causal relationship at this time, but there appears to be an increased number of SPMs in reports from several studies using lenalidomide maintenance. Current studies should be amended and future studies planned to better define the risk of SPMs and the risk factors and mechanisms for its development. Patients should be educated regarding this potential concern but the current use of lenalidomide should not generally be altered until further data are available. PMID:22851973

Secondary primary malignancies in multiple myeloma: an old NEMESIS revisited.

PubMed

Yang, Jay; Terebelo, Howard R; Zonder, Jeffrey A

2012-01-01

The treatment of myeloma has undergone extraordinary improvements in the past half century. These advances have been accompanied by a concern for secondary primary malignancies (SPMs). It has been known for decades that extended therapy with alkylating chemotherapy agents, such as melphalan, carries an increased risk of therapy-related myelodysplastic syndrome and/or acute myeloid leukemia (t-MDS/AML), with a cumulative risk as high as 10-15%. High-dose chemotherapy with autologous stem cell support became widely accepted for myeloma in the 1990s. Despite the use of high doses of melphalan, the risk of t-MDS/AML with this procedure is estimated to be less than 5%, with much of this risk attributable to pretransplant therapy. Recently, lenalidomide has come under scrutiny for its possible association with SPMs. It is too soon to declare a causal relationship at this time, but there appears to be an increased number of SPMs in reports from several studies using lenalidomide maintenance. Current studies should be amended and future studies planned to better define the risk of SPMs and the risk factors and mechanisms for its development. Patients should be educated regarding this potential concern but the current use of lenalidomide should not generally be altered until further data are available.

Revisiting the effects of hydrodynamic sorting and sedimentary recycling on chemical weathering indices

NASA Astrophysics Data System (ADS)

Guo, Yulong; Yang, Shouye; Su, Ni; Li, Chao; Yin, Ping; Wang, Zhongbo

2018-04-01

Although the proxies based on elemental geochemistry of siliciclastic sediments have been well developed to indicate the intensity of chemical weathering in various catchments, their geological indications and limitations, and especially how the differentiation of minerals and sediment grain size influences the applications of these proxies needs more clarification. This paper investigates the interactive effects of weathering, hydraulic sorting and sedimentary recycling on river sediment chemistry, and further validates the application of various weathering indices by measuring mineralogical and geochemical compositions of bank sediments and suspended particulate matters (SPMs) from five rivers in East China bearing various sizes, geologic settings and climatic regimes. For a specific river, the silicate weathering intensity registered in the fine SPMs is systematically stronger than that in the coarse-grained bank sediments. Most of the weathering indices not only reflect the integrated weathering history of various catchments but also depend on hydraulic sorting effect during sediment transport and depositional processes. The correlation between CIA (chemical index of alteration) and WIP (weathering index of Parker) offers an approach to predict the weathering trends of the fine SPMs, coarse bank sediments and recycled sediments under the influence of quartz dilution. To minimize the effects of hydrodynamic sorting and sedimentary recycling, we suggest that the fine sediments (e.g. SPMs and <2 μm fraction of bank sediments) in rivers can better reflect the average of present-day weathering crust in catchments and the weathered terrigenous materials into marginal seas and oceans.

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses.

PubMed

Chiurchiù, Valerio; Leuti, Alessandro; Dalli, Jesmond; Jacobsson, Anders; Battistini, Luca; Maccarrone, Mauro; Serhan, Charles N

2016-08-24

Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8(+) T cells and CD4(+) T helper 1 (TH1) and TH17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4(+) T cell differentiation into TH1 and TH17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3(+) regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2(-/-)) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2(-/-) mice or in vivo administration of resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation. Copyright © 2016, American Association for the Advancement of Science.

Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation.

PubMed

Arnardottir, Hildur H; Dalli, Jesmond; Norling, Lucy V; Colas, Romain A; Perretti, Mauro; Serhan, Charles N

2016-09-15

Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rvs) are a new family from the endogenous specialized proresolving mediators (SPMs) that actively stimulate resolution of inflammation. In this study, using lipid mediator metabololipidomics with murine joints we found a temporal regulation of endogenous SPMs during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series Rvs, for example, RvD1, RvD2, RvD3, and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared with self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis patients compared with healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores, and edema. Taken together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis. Copyright © 2016 by The American Association of Immunologists, Inc.

A maize spermine synthase 1 PEST sequence fused to the GUS reporter protein facilitates proteolytic degradation.

PubMed

Maruri-López, Israel; Rodríguez-Kessler, Margarita; Rodríguez-Hernández, Aída Araceli; Becerra-Flora, Alicia; Olivares-Grajales, Juan Elías; Jiménez-Bremont, Juan Francisco

2014-05-01

Polyamines are low molecular weight aliphatic compounds involved in various biochemical, cellular and physiological processes in all organisms. In plants, genes involved in polyamine biosynthesis and catabolism are regulated at transcriptional, translational, and posttranslational level. In this research, we focused on the characterization of a PEST sequence (rich in proline, glutamic acid, serine, and threonine) of the maize spermine synthase 1 (ZmSPMS1). To this aim, 123 bp encoding 40 amino acids of the C-terminal region of the ZmSPMS1 enzyme containing the PEST sequence were fused to the GUS reporter gene. This fusion was evaluated in Arabidopsis thaliana transgenic lines and onion monolayers transient expression system. The ZmSPMS1 PEST sequence leads to specific degradation of the GUS reporter protein. It is suggested that the 26S proteasome may be involved in GUS::PEST fusion degradation in both onion and Arabidopsis. The PEST sequences appear to be present in plant spermine synthases, mainly in monocots. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials?

PubMed

Fiala, Milan; Restrepo, Lucas; Pellegrini, Matteo

2018-01-01

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Coordinate metrology using scanning probe microscopes

NASA Astrophysics Data System (ADS)

Marinello, F.; Savio, E.; Bariani, P.; Carmignato, S.

2009-08-01

New positioning, probing and measuring strategies in coordinate metrology are needed for the accomplishment of true three-dimensional characterization of microstructures, with uncertainties in the nanometre range. In the present work, the implementation of scanning probe microscopes (SPMs) as systems for coordinate metrology is discussed. A new non-raster measurement approach is proposed, where the probe is moved to sense points along free paths on the sample surface, with no loss of accuracy with respect to traditional raster scanning and scan time reduction. Furthermore, new probes featuring long tips with innovative geometries suitable for coordinate metrology through SPMs are examined and reported.

Simulation of a synergistic six-post motion system on the flight simulator for advanced aircraft at NASA-Ames

NASA Technical Reports Server (NTRS)

Bose, S. C.; Parris, B. L.

1977-01-01

Motion system drive philosophy and corresponding real-time software have been developed for the purpose of simulating the characteristics of a typical synergistic Six-Post Motion System (SPMS) on the Flight Simulator for Advanced Aircraft (FSAA) at NASA-Ames which is a non-synergistic motion system. This paper gives a brief description of these two types of motion systems and the general methods of producing motion cues of the FSAA. An actuator extension transformation which allows the simulation of a typical SPMS by appropriate drive washout and variable position limiting is described.

Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice.

PubMed

Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong; Bang, Sangsu; Jordt, Sven-Eric; Maixner, William; Serhan, Charles N; Ji, Ru-Rong

2018-01-01

Mechanisms of pain resolution are largely unclear. Increasing evidence suggests that specialized pro-resolving mediators (SPMs), derived from fish oil docosahexaenoic acid (DHA), promote the resolution of acute inflammation and potently inhibit inflammatory and neuropathic pain. In this study, we examined the analgesic impact of DHA and DHA-derived SPMs in a mouse model of post-operative pain induced by tibial bone fracture (fPOP). Intravenous perioperative treatment with DHA (500 μg), resolvin D1 (RvD1, 500 ng) and maresin 1 (MaR1, 500 ng), 10 min and 24 h after the surgery, delayed the development of fPOP (mechanical allodynia and cold allodynia). In contrast, post-operative intrathecal (IT) administration of DHA (500 μg) 2 weeks after the surgery had no effects on established mechanical and cold allodynia. However, by direct comparison, IT post-operative treatment (500 ng) with neuroprotectin D1 (NPD1), MaR1, and D-resolvins, RvD1 and RvD5, but not RvD3 and RvD4, effectively reduced mechanical and cold allodynia. ELISA analysis showed that perioperative DHA treatment increased RvD1 levels in serum and spinal cord samples after bone fracture. Interestingly, sham surgery resulted in transient allodynia and increased RvD1 levels, suggesting a correlation of enhanced SPM levels with acute pain resolution after sham surgery. Our findings suggest that (1) perioperative treatment with DHA is effective in preventing and delaying the development of fPOP and (2) post-treatment with some SPMs can attenuate established fPOP. Our data also indicate that orthopedic surgery impairs SPM production. Thus, DHA and DHA-derived SPMs should be differentially supplemented for treating fPOP and improving recovery.

Controlled formation of GeSi nanostructures on pillar-patterned Si substrate

NASA Astrophysics Data System (ADS)

Zhou, Tong; Zeng, Ceng; Fan, Yongliang; Jiang, Zuimin; Xia, Jinsong; Zhong, Zhenyang; Fudan University Team; Huazhong University of Science; Technology Collaboration

2015-03-01

GeSi quantum nanostructures (QNs) have potential applications in optoelectronic devices due to their unique properties and compatibility with the sophisticated Si technology. However, the disadvantages of poor quantum efficiency of the GeSi QNs on flat Si (001) substrates hinder their optoelectronic applications. Today, numerous growth strategies have been proposed to control the formation of GeSi QNs in hope of improving the optoelectronic performances. One of the ways is to fabricate GeSi QNs on patterned substrates, where the GeSi QNs can be greatly manipulated in aspects of size, shape, composition, orientation and arrangement. Here, self-assembled GeSi QNs on periodic Si (001) sub-micro pillars (SPMs) are systematically studied. By controlling the growth conditions and the diameters of the SPMs, different GeSi QNs, including circularly arranged quantum dots (QDs), quantum rings (QRs), and quantum dot molecules (QDMs), are realized at the top edge of SMPs. Meanwhile, fourfold symmetric GeSi QDMs can be also obtained at the base edges of the SPMs. The promising features of self-assembled GeSi QNs are explained in terms of the surface chemical potential, which disclose the critical effect of surface morphology on the diffusion and the aggregation of Ge adatoms.

Digitally controlled analog proportional-integral-derivative (PID) controller for high-speed scanning probe microscopy

NASA Astrophysics Data System (ADS)

Dukic, Maja; Todorov, Vencislav; Andany, Santiago; Nievergelt, Adrian P.; Yang, Chen; Hosseini, Nahid; Fantner, Georg E.

2017-12-01

Nearly all scanning probe microscopes (SPMs) contain a feedback controller, which is used to move the scanner in the direction of the z-axis in order to maintain a constant setpoint based on the tip-sample interaction. The most frequently used feedback controller in SPMs is the proportional-integral (PI) controller. The bandwidth of the PI controller presents one of the speed limiting factors in high-speed SPMs, where higher bandwidths enable faster scanning speeds and higher imaging resolution. Most SPM systems use digital signal processor-based PI feedback controllers, which require analog-to-digital and digital-to-analog converters. These converters introduce additional feedback delays which limit the achievable imaging speed and resolution. In this paper, we present a digitally controlled analog proportional-integral-derivative (PID) controller. The controller implementation allows tunability of the PID gains over a large amplification and frequency range, while also providing precise control of the system and reproducibility of the gain parameters. By using the analog PID controller, we were able to perform successful atomic force microscopy imaging of a standard silicon calibration grating at line rates up to several kHz.

Digitally controlled analog proportional-integral-derivative (PID) controller for high-speed scanning probe microscopy.

PubMed

Dukic, Maja; Todorov, Vencislav; Andany, Santiago; Nievergelt, Adrian P; Yang, Chen; Hosseini, Nahid; Fantner, Georg E

2017-12-01

Nearly all scanning probe microscopes (SPMs) contain a feedback controller, which is used to move the scanner in the direction of the z-axis in order to maintain a constant setpoint based on the tip-sample interaction. The most frequently used feedback controller in SPMs is the proportional-integral (PI) controller. The bandwidth of the PI controller presents one of the speed limiting factors in high-speed SPMs, where higher bandwidths enable faster scanning speeds and higher imaging resolution. Most SPM systems use digital signal processor-based PI feedback controllers, which require analog-to-digital and digital-to-analog converters. These converters introduce additional feedback delays which limit the achievable imaging speed and resolution. In this paper, we present a digitally controlled analog proportional-integral-derivative (PID) controller. The controller implementation allows tunability of the PID gains over a large amplification and frequency range, while also providing precise control of the system and reproducibility of the gain parameters. By using the analog PID controller, we were able to perform successful atomic force microscopy imaging of a standard silicon calibration grating at line rates up to several kHz.

Sitting Posture Monitoring System Based on a Low-Cost Load Cell Using Machine Learning

PubMed Central

Roh, Jongryun; Park, Hyeong-jun; Lee, Kwang Jin; Hyeong, Joonho; Kim, Sayup

2018-01-01

Sitting posture monitoring systems (SPMSs) help assess the posture of a seated person in real-time and improve sitting posture. To date, SPMS studies reported have required many sensors mounted on the backrest plate and seat plate of a chair. The present study, therefore, developed a system that measures a total of six sitting postures including the posture that applied a load to the backrest plate, with four load cells mounted only on the seat plate. Various machine learning algorithms were applied to the body weight ratio measured by the developed SPMS to identify the method that most accurately classified the actual sitting posture of the seated person. After classifying the sitting postures using several classifiers, average and maximum classification rates of 97.20% and 97.94%, respectively, were obtained from nine subjects with a support vector machine using the radial basis function kernel; the results obtained by this classifier showed a statistically significant difference from the results of multiple classifications using other classifiers. The proposed SPMS was able to classify six sitting postures including the posture with loading on the backrest and showed the possibility of classifying the sitting posture even though the number of sensors is reduced. PMID:29329261

Improved identification of primary biological aerosol particles using single-particle mass spectrometry

DOE PAGES

Zawadowicz, Maria A.; Froyd, Karl D.; Murphy, Daniel M.; ...

2017-06-16

Measurements of primary biological aerosol particles (PBAP), especially at altitudes relevant to cloud formation, are scarce. Single-particle mass spectrometry (SPMS) has been used to probe aerosol chemical composition from ground and aircraft for over 20 years. Here we develop a method for identifying bioaerosols (PBAP and particles containing fragments of PBAP as part of an internal mixture) using SPMS. Here, we show that identification of bioaerosol using SPMS is complicated because phosphorus-bearing mineral dust and phosphorus-rich combustion by-products such as fly ash produce mass spectra with peaks similar to those typically used as markers for bioaerosol. We have developed a methodologymore » to differentiate and identify bioaerosol using machine learning statistical techniques applied to mass spectra of known particle types. This improved method provides far fewer false positives compared to approaches reported in the literature. The new method was then applied to two sets of ambient data collected at Storm Peak Laboratory and a forested site in Central Valley, California to show that 0.04–2 % of particles in the 200–3000 nm aerodynamic diameter range were identified as bioaerosol. In addition, 36–56 % of particles identified as biological also contained spectral features consistent with mineral dust, suggesting internal dust–biological mixtures.« less

Improved identification of primary biological aerosol particles using single-particle mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zawadowicz, Maria A.; Froyd, Karl D.; Murphy, Daniel M.

Measurements of primary biological aerosol particles (PBAP), especially at altitudes relevant to cloud formation, are scarce. Single-particle mass spectrometry (SPMS) has been used to probe aerosol chemical composition from ground and aircraft for over 20 years. Here we develop a method for identifying bioaerosols (PBAP and particles containing fragments of PBAP as part of an internal mixture) using SPMS. Here, we show that identification of bioaerosol using SPMS is complicated because phosphorus-bearing mineral dust and phosphorus-rich combustion by-products such as fly ash produce mass spectra with peaks similar to those typically used as markers for bioaerosol. We have developed a methodologymore » to differentiate and identify bioaerosol using machine learning statistical techniques applied to mass spectra of known particle types. This improved method provides far fewer false positives compared to approaches reported in the literature. The new method was then applied to two sets of ambient data collected at Storm Peak Laboratory and a forested site in Central Valley, California to show that 0.04–2 % of particles in the 200–3000 nm aerodynamic diameter range were identified as bioaerosol. In addition, 36–56 % of particles identified as biological also contained spectral features consistent with mineral dust, suggesting internal dust–biological mixtures.« less

Improved identification of primary biological aerosol particles using single-particle mass spectrometry

NASA Astrophysics Data System (ADS)

Zawadowicz, Maria A.; Froyd, Karl D.; Murphy, Daniel M.; Cziczo, Daniel J.

2017-06-01

Measurements of primary biological aerosol particles (PBAP), especially at altitudes relevant to cloud formation, are scarce. Single-particle mass spectrometry (SPMS) has been used to probe aerosol chemical composition from ground and aircraft for over 20 years. Here we develop a method for identifying bioaerosols (PBAP and particles containing fragments of PBAP as part of an internal mixture) using SPMS. We show that identification of bioaerosol using SPMS is complicated because phosphorus-bearing mineral dust and phosphorus-rich combustion by-products such as fly ash produce mass spectra with peaks similar to those typically used as markers for bioaerosol. We have developed a methodology to differentiate and identify bioaerosol using machine learning statistical techniques applied to mass spectra of known particle types. This improved method provides far fewer false positives compared to approaches reported in the literature. The new method was then applied to two sets of ambient data collected at Storm Peak Laboratory and a forested site in Central Valley, California to show that 0.04-2 % of particles in the 200-3000 nm aerodynamic diameter range were identified as bioaerosol. In addition, 36-56 % of particles identified as biological also contained spectral features consistent with mineral dust, suggesting internal dust-biological mixtures.

Specific interaction of postsynaptic densities with membrane rafts isolated from synaptic plasma membranes.

PubMed

Liu, Qian; Yao, Wei-Dong; Suzuki, Tatsuo

2013-06-01

Postsynaptic membrane rafts are believed to play important roles in synaptic signaling, plasticity, and maintenance. We recently demonstrated the presence, at the electron microscopic level, of complexes consisting of membrane rafts and postsynaptic densities (PSDs) in detergent-resistant membranes (DRMs) prepared from synaptic plasma membranes (SPMs) ( Suzuki et al., 2011 , J Neurochem, 119, 64-77). To further explore these complexes, here we investigated the nature of the binding between purified SPM-DRMs and PSDs in vitro. In binding experiments, we used SPM-DRMs prepared after treating SPMs with n-octyl-β-d-glucoside, because at concentrations of 1.0% or higher it completely separates SPM-DRMs and PSDs, providing substantially PSD-free unique SPM-DRMs as well as DRM-free PSDs. PSD binding to PSD-free DRMs was identified by mass spectrometry, Western blotting, and electron microscopy. PSD proteins were not incorporated into SPMs, and significantly less PSD proteins were incorporated into DRMs prepared from liver membranes, providing in vitro evidence that binding of PSDs to DRMs is specific and suggestion of the presence of specific interacting molecules. These specific interactions may have important roles in synaptic development, function, and plasticity in vivo. In addition, the binding system we developed may be a good tool to search for binding molecules and binding mechanisms between PSDs and rafts.

Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma.

PubMed

Krishnan, Amrita Y; Mei, Matthew; Sun, Can-Lan; Thomas, Sandra H; Teh, Jennifer Berano; Kang, Tongjun; Htut, Myo; Somlo, George; Sahebi, Firoozeh; Forman, Stephen J; Bhatia, Smita

2013-02-01

Recent studies demonstrate an increased risk of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving maintenance lenalidomide after autologous stem cell transplantation (ASCT). We explored the possibility of other risk factors driving post-ASCT SPMs in patients with MM through analysis of our large transplantation database in conjunction with our Long-Term Follow-Up Program. We conducted a retrospective cohort study of 841 consecutive patients with MM who underwent ASCT at City of Hope between 1989 and 2009, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during, and after ASCT. Median duration of follow-up for the entire cohort was 3.4 years (range, 0.3-19.9 years). Sixty cases with a total of 70 SPMs were identified. The overall cumulative incidence of SPMs was 7.4% at 5 years and 15.9% at 10 years when nonmelanoma skin cancers (NMSCs) were included and 5.3% at 5 years and 11.2% at 10 years when NMSCs were excluded. Multivariate analysis of the entire cohort revealed associations of both older age (≥55 years; relative risk, 2.3; P < .004) and race (non-Hispanic white; relative risk, 2.4; P = .01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend toward increased risk (odds ratio, 3.5; P = .15); however, an insufficient number of patients were treated with lenalidomide to allow us to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables but was accompanied by loss of statistical significance. This large single-institution analysis identified associations between race and older age and increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that might not be restricted to lenalidomide. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A Population-Based Study of Subsequent Primary Malignancies After Endometrial Cancer: Genetic, Environmental, and Treatment-Related Associations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Aaron P.; Neeley, E. Shannon; Werner, Theresa

2010-09-01

Purpose: To examine the risk of subsequent primary malignancies (SPMs) in women diagnosed with endometrial cancer. Methods and Materials: The National Cancer Institute's Survival, Epidemiology, and End Results database was used to determine the risk of SPM after endometrial cancer in 69,739 women diagnosed between 1973 and 2005. Standardized incidence ratios were calculated (observed/expected [O/E]) for SPM sites. Results: Median follow-up was 11.2 years, representing 757,567 person-years of follow-up. The risk of SPM was significantly increased for small intestine (O/E = 1.48; 99% confidence interval [CI], 1.03-2.05), colon (O/E = 1.16; CI, 1.09-1.24), vagina (O/E = 2.71; CI, 1.86-3.8), andmore » urinary bladder (O/E = 1.41; CI, 1.25-1.59) SPMs and decreased for oral cavity and pharynx (O/E = 0.75; CI, 0.6-0.93), lung and bronchus (O/E = 0.78; CI, 0.72-0.84), and esophagus (O/E = 0.58; CI, 0.37-0.86) SPMs. Patients receiving external-beam radiotherapy for endometrial cancer had an increased risk of colon (p < 0.001), bladder (p < 0.001), vagina (p = 0.04), and soft-tissue (p = 0.014) SPMs. Patients treated with brachytherapy had an increased risk of bladder SPM (p = 0.006). A positive bidirectional association with endometrial cancer was observed for colorectal cancer, with a negative bidirectional association for oropharyngeal and lung cancers. Conclusions: Genetic, environmental, and treatment-related factors influence SPM risk. Genetic factors may contribute to the increased risk of colorectal cancer. Smoking's negative effect on endometrial cancer risk factors might explain the decreased risk of lung and oropharyngeal cancer. Patients treated with radiotherapy likely have a small but significantly increased risk of bladder, vagina, colon, and soft-tissue SPM.« less

A population-based study of subsequent primary malignancies after endometrial cancer: genetic, environmental, and treatment-related associations.

PubMed

Brown, Aaron P; Neeley, E Shannon; Werner, Theresa; Soisson, Andrew Patrick; Burt, Randall W; Gaffney, David K

2010-09-01

To examine the risk of subsequent primary malignancies (SPMs) in women diagnosed with endometrial cancer. The National Cancer Institute's Survival, Epidemiology, and End Results database was used to determine the risk of SPM after endometrial cancer in 69,739 women diagnosed between 1973 and 2005. Standardized incidence ratios were calculated (observed/expected [O/E]) for SPM sites. Median follow-up was 11.2 years, representing 757,567 person-years of follow-up. The risk of SPM was significantly increased for small intestine (O/E = 1.48; 99% confidence interval [CI], 1.03-2.05), colon (O/E = 1.16; CI, 1.09-1.24), vagina (O/E = 2.71; CI, 1.86-3.8), and urinary bladder (O/E = 1.41; CI, 1.25-1.59) SPMs and decreased for oral cavity and pharynx (O/E = 0.75; CI, 0.6-0.93), lung and bronchus (O/E = 0.78; CI, 0.72-0.84), and esophagus (O/E = 0.58; CI, 0.37-0.86) SPMs. Patients receiving external-beam radiotherapy for endometrial cancer had an increased risk of colon (p < 0.001), bladder (p < 0.001), vagina (p = 0.04), and soft-tissue (p = 0.014) SPMs. Patients treated with brachytherapy had an increased risk of bladder SPM (p = 0.006). A positive bidirectional association with endometrial cancer was observed for colorectal cancer, with a negative bidirectional association for oropharyngeal and lung cancers. Genetic, environmental, and treatment-related factors influence SPM risk. Genetic factors may contribute to the increased risk of colorectal cancer. Smoking's negative effect on endometrial cancer risk factors might explain the decreased risk of lung and oropharyngeal cancer. Patients treated with radiotherapy likely have a small but significantly increased risk of bladder, vagina, colon, and soft-tissue SPM. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Second Primary Malignant Neoplasms and Survival in Adolescent and Young Adult Cancer Survivors.

PubMed

Keegan, Theresa H M; Bleyer, Archie; Rosenberg, Aaron S; Li, Qian; Goldfarb, Melanie

2017-11-01

Although the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age. To assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (<15 years) and older adult (≥40 years) patients with the same SPMs. This was a population-based, retrospective cohort study of patients with cancer in 13 Surveillance, Epidemiology and End Results regions in the United States diagnosed from 1992 to 2008 and followed through 2013. Data analysis was performed between June 2016 and January 2017. Five-year relative survival was calculated overall and for each cancer occurring as a PM or SPM by age at diagnosis. The impact of SPM status on cancer-specific death was examined using multivariable Cox proportional hazards regression. A total of 15 954 pediatric, 125 750 AYAs, and 878 370 older adult patients diagnosed as having 14 cancers occurring as a PM or SPM were included. Overall, 5-year survival after an SPM was 33.1% lower for children, 20.2% lower for AYAs, and 8.3% lower for older adults compared with a PM at the same age. For the most common SPMs in AYAs, the absolute difference in 5-year survival was 42% lower for secondary non-Hodgkin lymphoma, 19% for secondary breast carcinoma, 15% for secondary thyroid carcinoma, and 13% for secondary soft-tissue sarcoma. Survival by SPM status was significantly worse in younger vs older patients for thyroid, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, soft-tissue sarcoma, and central nervous system cancer. Adolescents and young adults with secondary Hodgkin lymphoma (hazard ratio [95% CI], 3.5 [1.7-7.1]); soft-tissue sarcoma (2.8 [2.1-3.9]); breast carcinoma (2.1 [1.8-2.4]); acute myeloid leukemia (1.9 [1.5-2.4]); and central nervous system cancer (1.8 [1.2-2.8]) experienced worse survival compared with AYAs with the same PMs. The adverse impact of SPMs on survival is substantial for AYAs and may partially explain the relative lack of survival improvement in AYAs compared with other age groups. The impact of a particular SPM diagnosis on survival may inform age-specific prevention, screening, treatment, and survivorship recommendations.

Multiple sclerosis in India: An institutional study.

PubMed

Singhal, Ankit; Bhatia, Rohit; Srivastava, M V Padma; Prasad, Kameshwar; Singh, Mamta Bhushan

2015-05-01

Few population based studies on multiple sclerosis have been published from India. There is an increasing demand to establish a nationwide MS registry in India especially in view of the percieved increased incidence and prevalence. To create a registry data base for all MS patients presenting at our institute and understand the disease characteristics in our population and compare them with the published reports from the west. MS was diagnosed on the basis of clinical and imaging features (Revised McDonald׳s criteria 2010). Demographics, clinical data, treatment details and disease behavior were recorded over a follow up of one year. Descriptive analyses was performed. 101 patients (61 females) were recruited in the study period from June 2011 to December 2012. Mean age of the patients at the time of presentation was 33.3±9.2 years and mean duration of illness was 5.98±4.95. 68.4% patients had RRMS, 16.8% had SPMS whereas 14.8% patients had PPMS. Site(s) involved in first relapse was spinal cord in 43.7% patients followed by brainstem 25.3% and optic nerve in 24.1% patients. Mean number of relapses were 3.26±2.026. Mean EDSS at the time of presentation was 3.20±2.11. Overall, 55.44% patients took DMT at some point during their course of disease. No significant differences were observed between our patient characteristics when compared to publications from west. Demographic data in the present study are comparable to those reported in population-based epidemiological studies from west. A nationwide registry network will help establish stronger data on incidence, prevalence and disease profile of MS in India. Copyright © 2015 Elsevier B.V. All rights reserved.

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

PubMed

Kallaur, Ana Paula; Oliveira, Sayonara Rangel; Simão, Andréa Name Colado; Alfieri, Daniela Frizon; Flauzino, Tamires; Lopes, Josiane; de Carvalho Jennings Pereira, Wildea Lice; de Meleck Proença, Caio; Borelli, Sueli Donizete; Kaimen-Maciel, Damacio Ramón; Maes, Michael; Reiche, Edna Maria Vissoci

2017-05-01

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.

PubMed

Liu, Yaou; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Liu, Zheng; Dong, Huiqing; Weiler, Florian; Hahn, Horst K; Shi, Fu-Dong; Butzkueven, Helmut; Barkhof, Frederik; Li, Kuncheng

2018-01-01

To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

PubMed

Fox, Robert J; Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-11-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

PubMed Central

Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-01-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. PMID:22917690

Strong-potential Born calculations for 1s-1s electron capture from atoms by protons

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, J.H.; Kletke, R.E.; Sil, N.C.

1985-08-01

The strong-potential Born (SPB) approximation is examined by comparing various SPB calculations of high-velocity 1s-1s electron capture cross sections with one another and with experimental data. Above about 1 MeV, calculations using the SPB method of McGuire and Sil (SPMS) (Phys. Rev. A 28, 3679 (1983)) are in good agreement with total-cross-section observations for protons on H, He, C, Ne, and Ar as expected. For p+H and p+He, the SPB full-peaking (SPB-FP) approximation of Macek and Alston (Phys. Rev. A 26, 250 (1982)) and the SPB transverse-peaking (SPB-TP) approximation of Alston (Phys. Rev. A 27, 2342 (1982)) differ from ourmore » SPMS total cross sections by typically a factor of 2, as expected from general validity criteria. However, the differential cross sections at very forward angles (well within the Thomas angle) are the same in SPMS, SPB-FP, and SPB-TP methods in all cases. Below 1 MeV, cross sections obtained with use of various SPB methods differ considerably from one another, placing a limit of validity for these SPB calculations. We also suggest that in the gap between those energies where continuum intermediate states simply dominate, and above those energies where bound intermediate states simply dominate, detailed conceptual understanding of electron capture is incomplete.« less

Distribution and dissipation pathways of nonylphenol polyethoxylates in the Yellow River: Site investigation and lab-scale studies.

PubMed

Wang, Lei; Wu, Yinghong; Sun, Hongwen; Xu, Jian; Dai, Shugui

2006-09-01

Spatial distribution of nonylphenol polyethoxylates (NPEOs) and nonylphenol (NP) was investigated in a field study in Lanzhou Reach of the Yellow River. NPEOs and their metabolites were found in the river, with the maximum dissolved concentrations of 6.38 nmol/L for NPEOs, 0.19 nmol/L for nonylphenol ethoxy acetic acids (NPECs) and 0.79 nmol/L for NP, respectively. The maximum concentrations in the sediment and suspended particle samples were 1.50 and 5.09 nmol/g for NPEOs and NP, respectively. The effects of particles, light and microorganism on the dissipation of NPEOs in the river water were investigated based on lab-scale experiments. When natural particles were removed, 72% and 22% degradation of NPEOs were achieved at 120 h in non-sterile and sterile conditions with light, respectively. Different concentrations of NPECs were also observed in these experiments. When suspended particle matters (SPMs) were present, about 38-50% of NPEOs were sorbed to the particulate phase in only 1 h. As a result, the degradation of NPEOs and production of NPECs were inhibited. However, the combined sorption and degradation in the presence of SPMs resulted in lower dissolved NPEO concentrations than those in the absence of SPMs. Biodegradation was the most important pathway for NPEOs degradation in the river water, while NPECs seemed to be produced through both biological and abiological pathways.

Elevated risk of human papillomavirus-related second cancers in survivors of anal canal cancer.

PubMed

Nelson, Rebecca A; Lai, Lily L

2017-10-15

Over the last decade, the causal link between human papillomavirus (HPV) infection and squamous cell carcinoma of the anus (SCCA) has been well described. Because HPV infection in one site is often associated with other sites of infection, it then follows that patients with SCCA may have an increased risk of additional HPV-related cancers. Identifying and targeting at-risk sites through cancer screening and surveillance may help to guide best practices. The current study sought to ascertain sites and risk of HPV-related second primary malignancies (SPMs) in survivors of SCCA. Using population-based data from 1992 through 2012, the authors identified patients with SCCA and determined their risk of HPV-related SPMs, including anal, oral, and genital cancers. Standardized incidence ratios (SIRs), defined as observed to expected cases, were calculated to determine excess risk. Of 10,537 patients with SCCA, 416 developed HPV-related SPMs, which corresponded to an overall SIR of 21.5 (99% confidence interval [99% CI], 19.0-24.2). Men were found to have a higher SIR (35.8; 99% CI, 30.7-41.6) compared with women (12.8; 99% CI, 10.4-15.5). SIRs for a second SCCA were markedly higher in men (127.5; 99% CI, 108.1-149.2) compared with women (47.0; 99% CI, 34.7-62.1), whereas SIRs for oral cavity and pharyngeal cancers were elevated in men (3.1; 99% CI, 1.5-5.7) and women (4.4; 99% CI, 1.5-9.7). SIRs for sex-specific sites also were elevated, with male genital cancers having an SIR of 19.6 (99% CI, 8.7-37.6) and female genital cancers an SIR of 8.3 (99% CI, 6.1-11.0). Patients with index SCCA are at an increased risk of subsequent HPV-related SPMs. The elevated risk is most striking in patients with second primary SCCAs; however, the risk of second cancers also appears to be increased in other HPV-related sites. Cancer 2017;123:4013-21. © 2017 American Cancer Society. © 2017 American Cancer Society.

Pixel-based skin segmentation in psoriasis images.

PubMed

George, Y; Aldeen, M; Garnavi, R

2016-08-01

In this paper, we present a detailed comparison study of skin segmentation methods for psoriasis images. Different techniques are modified and then applied to a set of psoriasis images acquired from the Royal Melbourne Hospital, Melbourne, Australia, with aim of finding the best technique suited for application to psoriasis images. We investigate the effect of different colour transformations on skin detection performance. In this respect, explicit skin thresholding is evaluated with three different decision boundaries (CbCr, HS and rgHSV). Histogram-based Bayesian classifier is applied to extract skin probability maps (SPMs) for different colour channels. This is then followed by using different approaches to find a binary skin map (SM) image from the SPMs. The approaches used include binary decision tree (DT) and Otsu's thresholding. Finally, a set of morphological operations are implemented to refine the resulted SM image. The paper provides detailed analysis and comparison of the performance of the Bayesian classifier in five different colour spaces (YCbCr, HSV, RGB, XYZ and CIELab). The results show that histogram-based Bayesian classifier is more effective than explicit thresholding, when applied to psoriasis images. It is also found that decision boundary CbCr outperforms HS and rgHSV. Another finding is that the SPMs of Cb, Cr, H and B-CIELab colour bands yield the best SMs for psoriasis images. In this study, we used a set of 100 psoriasis images for training and testing the presented methods. True Positive (TP) and True Negative (TN) are used as statistical evaluation measures.

A multistage crucible of revision and approval shapes IPCC policymaker summaries.

PubMed

Mach, Katharine J; Freeman, Patrick T; Mastrandrea, Michael D; Field, Christopher B

2016-08-01

Intergovernmental Panel on Climate Change (IPCC) member governments approve each report's summary for policymakers (SPM) by consensus, discussing and agreeing on each sentence in a plenary session with scientist authors. A defining feature of IPCC assessment, the governmental approval process builds joint ownership of current knowledge by scientists and governments. The resulting SPM revisions have been extensively discussed in anecdotes, interviews, and perspectives, but they have not been comprehensively analyzed. We provide an in-depth evaluation of IPCC SPM revisions, establishing an evidential basis for understanding their nature. Revisions associated with governmental review and approval generally expand SPMs, with SPM text growing by 17 to 53% across recent assessment reports. Cases of high political sensitivity and failure to reach consensus are notable exceptions, resulting in SPM contractions. In contrast to recent claims, we find that IPCC SPMs are as readable, for multiple metrics of reading ease, as other professionally edited assessment summaries. Across reading-ease metrics, some SPMs become more readable through governmental review and approval, whereas others do not. In an SPM examined through the entire revision process, most revisions associated with governmental review and approval occurred before the start of the government-approval plenary session. These author revisions emphasize clarity, scientific rigor, and explanation. In contrast, the subsequent plenary revisions place greater emphasis especially on policy relevance, comprehensiveness of examples, and nuances of expert judgment. Overall, the value added by the IPCC process emerges in a multistage crucible of revision and approval, as individuals together navigate complex science-policy terrain.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

PubMed

Giovannoni, Gavin; Cutter, Gary; Sormani, Maria Pia; Belachew, Shibeshih; Hyde, Robert; Koendgen, Harold; Knappertz, Volker; Tomic, Davorka; Leppert, David; Herndon, Robert; Wheeler-Kingshott, Claudia A M; Ciccarelli, Olga; Selwood, David; di Cantogno, Elisabetta Verdun; Ben-Amor, Ali-Frederic; Matthews, Paul; Carassiti, Daniele; Baker, David; Schmierer, Klaus

2017-02-01

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials. Copyright © 2016 Elsevier B.V. All rights reserved.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

PubMed

D'hooghe, M B; Haentjens, P; Nagels, G; Garmyn, M; De Keyser, J

2012-04-01

Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Chronic Cerebrospinal Vascular Insufficiency Is Not Associated with HLA DRB1*1501 Status in Multiple Sclerosis Patients

PubMed Central

Weinstock-Guttman, Bianca; Zivadinov, Robert; Cutter, Gary; Tamaño-Blanco, Miriam; Marr, Karen; Badgett, Darlene; Carl, Ellen; Elfadil, Makki; Kennedy, Cheryl; Benedict, Ralph H. B.; Ramanathan, Murali

2011-01-01

Background Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients. Methodology/Principal Findings This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients. Conclusions/Significance The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS. PMID:21340025

Linguistic analysis of IPCC summaries for policymakers and associated coverage

NASA Astrophysics Data System (ADS)

Barkemeyer, Ralf; Dessai, Suraje; Monge-Sanz, Beatriz; Renzi, Barbara Gabriella; Napolitano, Giulio

2016-03-01

The Intergovernmental Panel on Climate Change (IPCC) Summary for Policymakers (SPM) is the most widely read section of IPCC reports and the main springboard for the communication of its assessment reports. Previous studies have shown that communicating IPCC findings to a variety of scientific and non-scientific audiences presents significant challenges to both the IPCC and the mass media. Here, we employ widely established sentiment analysis tools and readability metrics to explore the extent to which information published by the IPCC differs from the presentation of respective findings in the popular and scientific media between 1990 and 2014. IPCC SPMs clearly stand out in terms of low readability, which has remained relatively constant despite the IPCC’s efforts to consolidate and readjust its communications policy. In contrast, scientific and quality newspaper coverage has become increasingly readable and emotive. Our findings reveal easy gains that could be achieved in making SPMs more accessible for non-scientific audiences.

Efficient Imaging and Real-Time Display of Scanning Ion Conductance Microscopy Based on Block Compressive Sensing

NASA Astrophysics Data System (ADS)

Li, Gongxin; Li, Peng; Wang, Yuechao; Wang, Wenxue; Xi, Ning; Liu, Lianqing

2014-07-01

Scanning Ion Conductance Microscopy (SICM) is one kind of Scanning Probe Microscopies (SPMs), and it is widely used in imaging soft samples for many distinctive advantages. However, the scanning speed of SICM is much slower than other SPMs. Compressive sensing (CS) could improve scanning speed tremendously by breaking through the Shannon sampling theorem, but it still requires too much time in image reconstruction. Block compressive sensing can be applied to SICM imaging to further reduce the reconstruction time of sparse signals, and it has another unique application that it can achieve the function of image real-time display in SICM imaging. In this article, a new method of dividing blocks and a new matrix arithmetic operation were proposed to build the block compressive sensing model, and several experiments were carried out to verify the superiority of block compressive sensing in reducing imaging time and real-time display in SICM imaging.

Space pruning monotonic search for the non-unique probe selection problem.

PubMed

Pappalardo, Elisa; Ozkok, Beyza Ahlatcioglu; Pardalos, Panos M

2014-01-01

Identification of targets, generally viruses or bacteria, in a biological sample is a relevant problem in medicine. Biologists can use hybridisation experiments to determine whether a specific DNA fragment, that represents the virus, is presented in a DNA solution. A probe is a segment of DNA or RNA, labelled with a radioactive isotope, dye or enzyme, used to find a specific target sequence on a DNA molecule by hybridisation. Selecting unique probes through hybridisation experiments is a difficult task, especially when targets have a high degree of similarity, for instance in a case of closely related viruses. After preliminary experiments, performed by a canonical Monte Carlo method with Heuristic Reduction (MCHR), a new combinatorial optimisation approach, the Space Pruning Monotonic Search (SPMS) method, is introduced. The experiments show that SPMS provides high quality solutions and outperforms the current state-of-the-art algorithms.

Suitability of customer relationship management systems for the management of study participants in biomedical research.

PubMed

Schwanke, J; Rienhoff, O; Schulze, T G; Nussbeck, S Y

2013-01-01

Longitudinal biomedical research projects study patients or participants over a course of time. No IT solution is known that can manage study participants, enhance quality of data, support re-contacting of participants, plan study visits, and keep track of informed consent procedures and recruitments that may be subject to change over time. In business settings management of personal is one of the major aspects of customer relationship management systems (CRMS). To evaluate whether CRMS are suitable IT solutions for study participant management in biomedical research. Three boards of experts in the field of biomedical research were consulted to get an insight into recent IT developments regarding study participant management systems (SPMS). Subsequently, a requirements analysis was performed with stakeholders of a major biomedical research project. The successive suitability evaluation was based on the comparison of the identified requirements with the features of six CRMS. Independently of each other, the interviewed expert boards confirmed that there is no generic IT solution for the management of participants. Sixty-four requirements were identified and prioritized in a requirements analysis. The best CRMS was able to fulfill forty-two of these requirements. The non-fulfilled requirements demand an adaption of the CRMS, consuming time and resources, reducing the update compatibility, the system's suitability, and the security of the CRMS. A specific solution for the SPMS is favored instead of a generic and commercially-oriented CRMS. Therefore, the development of a small and specific SPMS solution was commenced and is currently on the way to completion.

A multistage crucible of revision and approval shapes IPCC policymaker summaries

PubMed Central

Mach, Katharine J.; Freeman, Patrick T.; Mastrandrea, Michael D.; Field, Christopher B.

2016-01-01

Intergovernmental Panel on Climate Change (IPCC) member governments approve each report’s summary for policymakers (SPM) by consensus, discussing and agreeing on each sentence in a plenary session with scientist authors. A defining feature of IPCC assessment, the governmental approval process builds joint ownership of current knowledge by scientists and governments. The resulting SPM revisions have been extensively discussed in anecdotes, interviews, and perspectives, but they have not been comprehensively analyzed. We provide an in-depth evaluation of IPCC SPM revisions, establishing an evidential basis for understanding their nature. Revisions associated with governmental review and approval generally expand SPMs, with SPM text growing by 17 to 53% across recent assessment reports. Cases of high political sensitivity and failure to reach consensus are notable exceptions, resulting in SPM contractions. In contrast to recent claims, we find that IPCC SPMs are as readable, for multiple metrics of reading ease, as other professionally edited assessment summaries. Across reading-ease metrics, some SPMs become more readable through governmental review and approval, whereas others do not. In an SPM examined through the entire revision process, most revisions associated with governmental review and approval occurred before the start of the government-approval plenary session. These author revisions emphasize clarity, scientific rigor, and explanation. In contrast, the subsequent plenary revisions place greater emphasis especially on policy relevance, comprehensiveness of examples, and nuances of expert judgment. Overall, the value added by the IPCC process emerges in a multistage crucible of revision and approval, as individuals together navigate complex science-policy terrain. PMID:27532046

Medical decision-making capacity and its cognitive predictors in progressive MS: Preliminary evidence.

PubMed

Gerstenecker, Adam; Lowry, Kathleen; Myers, Terina; Bashir, Khurram; Triebel, Kristen L; Martin, Roy C; Marson, Daniel C

2017-09-15

Medical decision-making capacity (MDC) refers to the ability to make informed decisions about treatment and declines in cognition are associated with declines in MDC across multiple disease entities. However, although it is well known that cognitive impairment is prevalent in multiple sclerosis (MS), little is known about MDC in the disease. Data from 22 persons with progressive MS and 18 healthy controls were analyzed. All diagnoses were made by a board-certified neurologist with experience in MS. All study participants were administered a vignette-based measure of MDC and also a neuropsychological battery. Performance on three MDC consent standards (i.e., Appreciation, Reasoning, Understanding) was significantly lower for people with progressive MS as compared to healthy controls. In the progressive MS group, verbal fluency was the primary cognitive predictor for both Reasoning and Understanding consent standards. Verbal learning and memory was the primary cognitive predictor for Appreciation. MS severity was not significantly correlated with any MDC variable. MDC is a complex and cognitively mediated functional ability that is impaired in many people with progressive MS. Verbal measures of fluency and memory are strongly associated with MDC performances in the current sample of people with MS and could potentially be utilized to quickly screen for MDC impairment in MS. Copyright © 2017 Elsevier B.V. All rights reserved.

Multiple sclerosis - etiology and diagnostic potential.

PubMed

Kamińska, Joanna; Koper, Olga M; Piechal, Kinga; Kemona, Halina

2017-06-30

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of autoimmune originate. The main agents responsible for the MS development include exogenous, environmental, and genetic factors. MS is characterized by multifocal and temporally scattered central nervous system (CNS) damage which lead to the axonal damage. Among clinical courses of MS it can be distinguish relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPSM), primary progressive multiple sclerosis (PPMS), and progressive-relapsing multiple sclerosis (RPMS). Depending on the severity of signs and symptoms MS can be described as benign MS or malignant MS. MS diagnosis is based on McDonald's diagnostic criteria, which link clinical manifestation with characteristic lesions demonstrated by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and visual evoked potentials. Among CSF laboratory tests used to the MS diagnosis are applied: Tibbling & Link IgG index, reinbegrams, and CSF isoelectrofocusing for oligoclonal bands detection. It should be emphasized, that despite huge progress regarding MS as well as the availability of different diagnostics methods this disease is still a diagnostic challenge. It may result from fact that MS has diverse clinical course and there is a lack of single test, which would be of appropriate diagnostic sensitivity and specificity for quick and accurate diagnosis.

Specialized Pro-resolving Mediators Regulate Alveolar Fluid Clearance during Acute Respiratory Distress Syndrome

PubMed Central

Wang, Qian; Yan, Song-Fan; Hao, Yu; Jin, Sheng-Wei

2018-01-01

Objective: Acute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by the injury of alveolar epithelium, which impairs active fluid transport in the lung, and impedes the reabsorption of edema fluid from the alveolar space. This review aimed to discuss the role of pro-resolving mediators on the regulation of alveolar fluid clearance (AFC) in ARDS. Data Sources: Articles published up to September 2017 were selected from the PubMed, with the keywords of “alveolar fluid clearance” or “lung edema” or “acute lung injury” or “acute respiratory distress syndrome”, and “specialized pro-resolving mediators” or “lipoxin” or “resolvin” or “protectin” or “maresin” or “alveolar epithelial cells” or “aspirin-triggered lipid mediators” or “carbon monoxide and heme oxygenase” or “annexin A1”. Study Selection: We included all relevant articles published up to September 2017, with no limitation of study design. Results: Specialized pro-resolving mediators (SPMs), as the proinflammatory mediators, not only upregulated epithelial sodium channel, Na,K-ATPase, cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporins levels, but also improved Na,K-ATPase activity to promote AFC in ARDS. In addition to the direct effects on ion channels and pumps of the alveolar epithelium, the SPMs also inhibited the inflammatory cytokine expression and improved the alveolar epithelial cell repair to enhance the AFC in ARDS. Conclusions: The present review discusses a novel mechanism for pulmonary edema fluid reabsorption. SPMs might provide new opportunities to design “reabsorption-targeted” therapies with high degrees of precision in controlling ALI/ARDS. PMID:29664060

A Decade of Experience in Primary Prevention of Clostridium difficile Infection at a Community Hospital Using the Probiotic Combination Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+).

PubMed

Maziade, Pierre-Jean; Pereira, Pascale; Goldstein, Ellie J C

2015-05-15

In August 2003, the 284-bed community hospital Pierre-Le Gardeur (PLGH) in Quebec experienced a major outbreak associated with the Clostridium difficile NAP1/027/BI strain. Augmented standard preventive measures (SPMs) were not able to control this outbreak. It was decided in February 2004 to give to every adult inpatient on antibiotics, without any exclusion, a probiotic (Bio-K+: Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2) within 12 hours of the antibiotic prescription. Augmented SPMs were continued. The use of the probiotic in addition to SPMs was associated with a marked reduction of C. difficile infection (CDI). During the 10 years of observation, 44 835 inpatients received Bio-K+, and the CDI rate at PLGH declined from 18.0 cases per 10,000 patient-days and remained at low mean levels of 2.3 cases per 10,000 patient-days. Additionally, 10-year data collected by the Ministry of Health in Quebec comparing the CDI rate between Quebec hospitals showed that CDI rates at PLGH were consistently and continuously lower compared with those at similar hospitals. Blood cultures were monitored at PLGH for Lactobacillus bacteremia through the 10 years' experience, and no Lactobacillus bacteremias were detected. Despite the limitation of an observational study, we concluded that the probiotic Bio-K+ was safe and effective in decreasing our primary CDI rate. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A cluster of immunoresolvents links coagulation to innate host defense in human blood.

PubMed

Norris, Paul C; Libreros, Stephania; Chiang, Nan; Serhan, Charles N

2017-08-01

Blood coagulation is a protective response that prevents excessive bleeding upon blood vessel injury. We investigated the relationship between coagulation and the resolution of inflammation and infection by lipid mediators (LMs) through metabololipidomics-based profiling of human whole blood (WB) during coagulation. We identified temporal clusters of endogenously produced prothrombotic and proinflammatory LMs (eicosanoids), as well as specialized proresolving mediators (SPMs). In addition to eicosanoids, a specific SPM cluster was identified that consisted of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B 4 , and maresin 1, each of which was present at bioactive concentrations (0.1 to 1 nM). Removal of adenosine from the coagulating blood markedly enhanced the amounts of SPMs produced and further increased the biosynthesis of RvD3, RvD4, and RvD6. The cyclooxygenase inhibitors celecoxib and indomethacin, which block the production of thromboxanes and prostanoids, did not block the production of clot-driven SPMs. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targeted leukocytes at the single-cell level, directly activating ERK and CREB signaling in neutrophils and CD14 + monocytes. Treatment of human WB with the components of this SPM cluster enhanced both the phagocytosis and killing of Escherichia coli by leukocytes. Together, these data identify a proresolving LM circuit, including endogenous molecular brakes and accelerators, which promoted host defense. These temporal LM-SPM clusters can provide accessible metabolomic profiles for precision and personalized medicine. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

How IPCC Science-Policy Interactions Shape Its Policymaker Summaries

NASA Astrophysics Data System (ADS)

Mach, K. J.; Freeman, P. T.; Mastrandrea, M.; Field, C. B.

2016-12-01

Government approval is a defining feature of the Intergovernmental Panel on Climate Change (IPCC) assessment process. In plenary sessions with scientist authors, IPCC member governments discuss and agree each sentence of every report's summary for policymakers (SPM). This consensus-based approval builds joint ownership of scientific knowledge by both scientists and governments. The approval process and its resulting SPM revisions have received extensive attention in published anecdotes and perspectives, but without comprehensive evaluation to date. We present the results of an in-depth analysis of IPCC SPM revisions, providing an evidence basis for understanding a complex science-policy interaction. Revisions resulting from governmental review and approval expand SPMs. SPM text lengthens by 17 to 53% in recent assessment summaries. Political sensitivities and associated failures of consensus have led to prominent exceptions resulting in SPM contractions. Contrasting recent assertions, we find IPCC SPMs to be as readable as other professionally edited assessment summaries, for multiple measures of reading ease. Across metrics, some SPMs, but not all, become more readable through the revision process. We additionally examine each revision in an SPM for which we have deep familiarity. Most of the SPM's revisions occur prior to the in-person government-approval session, and they emphasize different purposes compared to revisions made during the approval session. Revisions prior to the in-person session largely pertain to clarity, scientific rigor, and explanation, whereas the subsequent in-person government-approval revisions place more emphasis on policy relevance, comprehensiveness of examples, and nuances of expert judgment. The value added in the IPCC government-approval process emerges through multiple stages of revision and approval, as scientists and governments together navigate a complex science-policy interaction.

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

PubMed

Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

2016-11-01

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recent Progress and Emerging Issues in Measuring and Modeling Biomass Burning Emissions

NASA Astrophysics Data System (ADS)

Yokelson, R. J.; Stockwell, C.; Veres, P. R.; Hatch, L. E.; Barsanti, K. C.; Simpson, I. J.; Blake, D. R.; Alvarado, M.; Kreidenweis, S. M.; Robinson, A. L.; Akagi, S. K.; McMeeking, G. R.; Stone, E.; Gilman, J.; Warneke, C.; Sedlacek, A. J.; Kleinman, L. I.

2013-12-01

Nine recent multi-PI campaigns (6 airborne, 3 laboratory) have quantified biomass burning emissions and the subsequent smoke evolution in unprecedented detail. Among these projects were the Fourth Fire Lab at Missoula Experiment (FLAME-4) and the DOE airborne campaign BBOP (Biomass Burning Observation Project). Between 2009 and 2013 a large selection of fuels and ecosystems were probed including: (1) 21 US prescribed fires in pine forests, chaparral, and shrublands; (2) numerous wildfires in the Pacific Northwest of the US; (3) 77 lab fires burning fuels collected from the sites of the prescribed fires; and (4) 158 lab fires burning authentic fuels in traditional cooking fires and advanced stoves; peat from Indonesia, Canada, and North Carolina; savanna grasses from Africa; temperate grasses from the US; crop waste from the US; rice straw from Taiwan, China, Malaysia, and California; temperate and boreal forest fuels collected in Montana and Alaska; chaparral fuels from California; trash; and tires. Instrumentation for gases included: FTIR, PTR-TOF-MS, 2D-GC and whole air sampling. Particle measurements included filter sampling (with IC, elemental carbon (EC), organic carbon (OC), and GC-MS) and numerous real-time measurements such as: HR-AMS (high-resolution aerosol MS), SP-AMS (soot particle AMS), SP2 (single particle soot photometer), SP-MS (single particle MS), ice nuclei, CCN (cloud condensation nuclei), water soluble OC, size distribution, and optical properties in the UV-VIS. New data include: emission factors for over 400 gases, black carbon (BC), brown carbon (BrC), organic aerosol (OA), ions, metals, EC, and OC; and details of particle morphology, mixing state, optical properties, size distributions, and cloud nucleating activity. Large concentrations (several ppm) of monoterpenes were present in fresh smoke. About 30-70% of the initially emitted gas-phase non-methane organic compounds were semivolatile and could not be identified with current technology. The detection rate for the sampled US prescribed fires was zero by burned area and <30% by active fire detection. Smoke evolution was measured for numerous gas-phase precursors and products, ozone, OA, ions, and BC and BrC mixing state. BC particles were coated within one hour and the smoke evolution was, in general, strongly impacted by the unidentified low volatility gases. An informative synthesis of lab and field fire data with fuels from the same sites was carried out. A preliminary comparison of wildfire and prescribed fire emissions will be presented. Novel schemes are under development to summarize the new emissions data for models, with limited mechanisms and parameterize fast, sub-grid processes. Key current issues to be discussed include: packaging/parameterizing the recent explosion of emissions/evolution data for use in model mechanisms; addressing fires not detected from space; addressing the large amount of unidentified semi-volatile gases emitted by all fires; and developing appropriate airborne and ground-based sampling scales/strategies for local-global models. We briefly summarize a recently funded project that will sample emissions and quantify biomass consumption by peat fires in Indonesia and a pending proposal for comprehensive sampling of cooking fires, brick kilns, garbage burning, diesel super-emitters, etc. in South Asia.

Living with Advanced MS

MedlinePlus

... whose health and safety are compromised by limited knowledge, understanding, and/or ability to access programs and benefits. Read More Read More Publication Managing Progressive MS An overview of symptom management, coping strategies when progressive MS makes the road ...

Defining active progressive multiple sclerosis.

PubMed

Sellebjerg, Finn; Börnsen, Lars; Ammitzbøll, Cecilie; Nielsen, Jørgen Erik; Vinther-Jensen, Tua; Hjermind, Lena Elisabeth; von Essen, Marina; Ratzer, Rikke Lenhard; Soelberg Sørensen, Per; Romme Christensen, Jeppe

2017-11-01

It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

Self-reported levels of education and disability progression in multiple sclerosis.

PubMed

D'hooghe, M B; Haentjens, P; Van Remoortel, A; De Keyser, J; Nagels, G

2016-12-01

The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Calibration of automatic performance measures - speed and volume data : volume 1, evaluation of the accuracy of traffic volume counts collected by microwave sensors.

DOT National Transportation Integrated Search

2015-09-01

Over the past few years, the Utah Department of Transportation (UDOT) has developed a system called the : Signal Performance Metrics System (SPMS) to evaluate the performance of signalized intersections. This system : currently provides data summarie...

MIF and D-DT are potential disease severity modifiers in male MS subjects

PubMed Central

Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley; Zhang, Ying; Nguyen, Ha; Kent, Gail; Li, Jia; Siu, Edwin; Frazer, Jenny; Piecychna, Marta; Du, Xin; Sreih, Antoine; Leng, Lin; Wiedrick, Jack; Caillier, Stacy J.; Offner, Halina; Oksenberg, Jorge R.; Yadav, Vijayshree; Bourdette, Dennis; Bucala, Richard; Vandenbark, Arthur A.

2017-01-01

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a −794CATT5–8 microsatellite repeat and a −173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes. PMID:28923927

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

PubMed

Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

2015-06-01

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

Exploring Wellness Interventions in Progressive Multiple Sclerosis: an Evidence-Based Review.

PubMed

Venasse, Myriam; Edwards, Thomas; Pilutti, Lara A

2018-04-10

There has been recent interest in the role of lifestyle and wellness-based approaches in the treatment and management of multiple sclerosis (MS). These approaches may be particularly relevant for patients with progressive MS, considering limited therapeutic options currently available. The purpose of this review is to examine the role of wellness-based interventions including exercise training, emotional well-being therapies, and dietary modification in patients with progressive MS. We conducted a literature search on the efficacy of wellness-based interventions in patients with progressive MS published between 1985 and July 2017. The level of evidence for each trial was evaluated using the American Academy of Neurology criteria. Overall, 21 articles reporting on 16 wellness-based interventions were identified: ten trials involved exercise training, three involved emotional wellness therapies, two involved dietary modification, and one was a combined wellness intervention. There is level C evidence (possibly effective; one class II study) for the efficacy of aerobic exercise training on cardiorespiratory fitness in patients with progressive MS. There is level B evidence (probably effective; one class I study) for the efficacy of mindfulness training on psychological distress, depression, anxiety, pain, and quality of life in patients with progressive MS. There is inadequate evidence (level U) for efficacy of dietary modification (one class III study and one class IV study) and combined wellness interventions involving exercise training, meditation, and dietary modification (one class IV study). High-quality research is needed to provide evidence-based recommendations for wellness behaviors and lifestyle change in patients with progressive MS.

Potential control of multiple sclerosis by cannabis and the endocannabinoid system.

PubMed

Pryce, Gareth; Baker, David

2012-08-01

For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS.

Symptomatic Therapy and Rehabilitation in Primary Progressive Multiple Sclerosis

PubMed Central

Khan, Fary; Amatya, Bhasker; Turner-Stokes, Lynne

2011-01-01

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system and a major cause of chronic neurological disability in young adults. Primary progressive MS (PPMS) constitutes about 10% of cases, and is characterized by a steady decline in function with no acute attacks. The rate of deterioration from disease onset is more rapid than relapsing remitting and secondary progressive MS types. Multiple system involvement at onset and rapid early progression have a worse prognosis. PPMS can cause significant disability and impact on quality of life. Recent studies are biased in favour of relapsing remitting patients as treatment is now available for them and they are more likely to be seen at MS clinics. Since prognosis for PPMS is worse than other types of MS, the focus of rehabilitation is on managing disability and enhancing participation, and application of a “neuropalliative” approach as the disease progresses. This chapter presents the symptomatic treatment and rehabilitation for persons with MS, including PPMS. A multidisciplinary approach optimizes the intermediate and long-term medical, psychological and social outcomes in this population. Restoration and maintenance of functional independence and societal reintegration, and issues relating to quality of life are addressed in rehabilitation processes. PMID:22013521

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

PubMed

Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

2016-01-01

Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

40 CFR Appendix A to Part 58 - Quality Assurance Requirements for SLAMS, SPMs and PSD Air Monitoring

Code of Federal Regulations, 2010 CFR

2010-07-01

... quality system in terms of the organizational structure, functional responsibilities of management and... more stringent requirements. Monitoring organizations may, based on their quality objectives, develop... infrequent work with EPA funds may combine the QMP with the QAPP based on negotiations with the funding...

Proteomic Analysis of Cerebrospinal Fluid in a Fulminant Case of Multiple Sclerosis

PubMed Central

Füvesi, Judit; Hanrieder, Jörg; Bencsik, Krisztina; Rajda, Cecilia; Kovács, S. Krisztián; Kaizer, László; Beniczky, Sándor; Vécsei, László; Bergquist, Jonas

2012-01-01

Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient’s death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject. PMID:22837721

MS5 Mediates Early Meiotic Progression and Its Natural Variants May Have Applications for Hybrid Production in Brassica napus

PubMed Central

Xin, Qiang; Shen, Yi; Li, Xi; Lu, Wei; Wang, Xiang; Han, Xue; Dong, Faming; Wan, Lili; Yang, Guangsheng; Cheng, Zhukuan

2016-01-01

During meiotic prophase I, chromatin undergoes dynamic changes to establish a structural basis for essential meiotic events. However, the mechanism that coordinates chromosome structure and meiotic progression remains poorly understood in plants. Here, we characterized a spontaneous sterile mutant MS5bMS5b in oilseed rape (Brassica napus) and found its meiotic chromosomes were arrested at leptotene. MS5 is preferentially expressed in reproductive organs and encodes a Brassica-specific protein carrying conserved coiled-coil and DUF626 domains with unknown function. MS5 is essential for pairing of homologs in meiosis, but not necessary for the initiation of DNA double-strand breaks. The distribution of the axis element-associated protein ASY1 occurs independently of MS5, but localization of the meiotic cohesion subunit SYN1 requires functional MS5. Furthermore, both the central element of the synaptonemal complex and the recombination element do not properly form in MS5bMS5b mutants. Our results demonstrate that MS5 participates in progression of meiosis during early prophase I and its allelic variants lead to differences in fertility, which may provide a promising strategy for pollination control for heterosis breeding. PMID:27194707

Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

PubMed

Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

2017-01-01

Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved in isolating synaptosomes, SPMs, and SJCs from brain so that these preparations can be used with new technological advances to address many as yet unanswered questions about the synapse and its remarkable activities in neuronal cell communication.

Interactions between different EEG frequency bands and their effect on alpha-fMRI correlations.

PubMed

de Munck, J C; Gonçalves, S I; Mammoliti, R; Heethaar, R M; Lopes da Silva, F H

2009-08-01

In EEG/fMRI correlation studies it is common to consider the fMRI BOLD as filtered version of the EEG alpha power. Here the question is addressed whether other EEG frequency components may affect the correlation between alpha and BOLD. This was done comparing the statistical parametric maps (SPMs) of three different filter models wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. EEG and fMRI were co-registered in a 30 min resting state condition in 15 healthy young subjects. Power variations in the delta, theta, alpha, beta and gamma bands were extracted from the EEG and used as regressors in a general linear model. Statistical parametric maps (SPMs) were computed using three different filter models, wherein either the free or the standard hemodynamic response functions (HRF) were used in combination with the full spectral bandwidth of the EEG. Results show that the SPMs of different EEG frequency bands, when significant, are very similar to that of the alpha rhythm. This is true in particular for the beta band, despite the fact that the alpha harmonics were discarded. It is shown that inclusion of EEG frequency bands as confounder in the fMRI-alpha correlation model has a large effect on the resulting SPM, in particular when for each frequency band the HRF is extracted from the data. We conclude that power fluctuations of different EEG frequency bands are mutually highly correlated, and that a multi frequency model is required to extract the SPM of the frequency of interest from EEG/fMRI data. When no constraints are put on the shapes of the HRFs of the nuisance frequencies, the correlation model looses so much statistical power that no correlations can be detected.

A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0654 TITLE: A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS...valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE Oct 2017 2. REPORT TYPE Annual 3. DATES COVERED 30...Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT

A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0653 TITLE: A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS...Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...compare the gut microbiome of subjects with RMS and PPMS. Major Task 1: To seek and obtain HRPO approval Major Task 2: Identification and

A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0654 TITLE: A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS...Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Major Tasks and subtasks: Aim#1: To compare the gut microbiome of subjects with RMS and PPMS. Major Task 1: To seek and obtain HRPO approval Major

A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0652 TITLE: A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS...0652 A Multidisciplinary Approach to Study the Role of the Gut Microbiome in Relapsing and Progressive MS 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...SOW, each Aim was subdivided into Major Tasks and subtasks: Aim#1: To compare the gut microbiome of subjects with RMS and PPMS. Major Task 1

Complement is activated in progressive multiple sclerosis cortical grey matter lesions.

PubMed

Watkins, Lewis M; Neal, James W; Loveless, Sam; Michailidou, Iliana; Ramaglia, Valeria; Rees, Mark I; Reynolds, Richard; Robertson, Neil P; Morgan, B Paul; Howell, Owain W

2016-06-22

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.

Associations of HLA DRB1 alleles with IgG oligoclonal bands and their influence on multiple sclerosis course and disability status.

PubMed

Balnytė, Renata; Rastenytė, Daiva; Vaitkus, Antanas; Skrodenienė, Erika; Vitkauskienė, Astra; Ulozienė, Ingrida

2016-01-01

Oligoclonal bands (OCB) may be associated with the genes of HLA complex, which allows to consider the possible interaction of genetic and immunological factors and its importance in the development and progression of multiple sclerosis (MS). The aim of this study was to evaluate the associations between HLA DRB1 alleles and oligoclonal bands (OCBs) in the disease course and disability of multiple sclerosis (MS) patients. This was a prospective study of 120 patients with MS. HLA DRB1 alleles were genotyped using the polymerase chain reaction. Matched cerebrospinal fluid (CSF) and plasma samples were analyzed using isoelectric focusing and IgG specific immunofixation to test for the presence of intrathecal specific OCB. HLA DRB1*08 allele was related to a lower degree of disability. Oligoclonal bands were an independent and significant factor that influenced disability status irrespective of HLA DRB1* 04, *07, *08, *13, *15 and *16 alleles. Age at the onset and duration of the disease were independent and significant factors for MS progression in all logistic regression models with each newly added HLA DRB1 allele. HLA DRB1*08 allele was related to 75% lower odds that relapsing remitting (RR) MS will change to a progressive course MS irrespective of the other factors investigated. Detection of OCBs in the CSF was associated with the higher possibility of RR MS progression in all cases, except when the *08 allele was present. OCBs had an influence on disability status, while HLA DRB1*08 allele was significantly associated with lower possibility that RR MS will change to progressive course MS. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions.

PubMed

Ciampi, E; Uribe-San-Martin, R; Vásquez, M; Ruiz-Tagle, A; Labbe, T; Cruz, J P; Lillo, P; Slachevsky, A; Reyes, D; Reyes, A; Cárcamo-Rodríguez, C

2018-02-01

Cognitive impairment is a relevant contributor of the medical and social burden in Progressive MS. Social Cognition, the neurocognitive processes underlying social interaction, has been explored mainly in European and North American cohorts, influencing social aspects of quality of life (QOL) of early MS patients and families. Few studies have studied Social Cognition in Progressive MS and the literature on its neuroanatomical bases or brain atrophy measurements is still scarce. To explore the relationship between Social Cognition performance and its correlations with traditional cognitive domains, brain atrophy and QOL in primary and secondary Progressive MS patients. Cross-sectional analysis including: mini-Social-Cognition-and-Emotional-Assessment (mini-SEA), neuropsychological battery, disability, depression, fatigue, QOL, and brain volume. Forty-three MS patients, 23 primary and 20 secondary Progressive, 65% women, mean age and disease duration of 57.2 and 15.7 years, respectively, with high levels of disability (median EDSS 6.0) and a widespread impairment in traditional domains (mostly episodic verbal/visual and working memories) were assessed. The Mini-SEA score was correlated with executive functions (cognitive shifts Rho:0.55; p = 0.001) analyzing the whole group, and with visual episodic memory (Rho:0.58, p = 0.009) in the primary Progressive MS group. Mini-SEA score was also correlated with total normalized grey matter volume (Rho:0.48; p = 0.004). Particularly, atrophy within bilateral cortical regions of orbitofrontal, insula and cerebellum, and right regions of fusiform gyrus and precuneus were significantly associated with higher Social Cognition impairment. In this cohort, QOL was not correlated with Social Cognition, but with EDSS, fatigue and depression. In Progressive MS, Social Cognition is directly correlated with traditional cognitive domains such as executive function and episodic memory. It is also associated with global grey matter atrophy and regional atrophy within associative visual and executive cortical areas, but no correlations with QOL were found in this cohort. These findings may contribute to the understanding of the pathological bases behind Social Cognition in Progressive MS. Copyright © 2018 Elsevier B.V. All rights reserved.

The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis

PubMed Central

Holloman, Jameson P; Ho, Calvin C; Hukki, Arushi; Huntley, Jennifer L; Gallicano, G Ian

2013-01-01

This article examines the current use and future implications of stem cell therapy in treating Multiple Sclerosis (MS). MS is the most common neurological disease in young adults, affecting approximately two million people worldwide. Currently there is no cure for MS. The standard treatment of MS involves disease-modifying drugs, which work to alleviate the symptoms of MS. However, these drugs carry adverse side effects and are ineffective in preventing disease progression in many MS patients. Hematopoietic stem cell transplantation (HSCT) was first used in 1995 to treat patients with severe rapidly progressing MS. The HSCT treatment protocol has evolved into a less intense conditioning regimen that is currently demonstrating efficacy in treating patients with variable disease severity—with best results in early-stage rapidly progressing MS patients with active CNS inflammation. Mesenchymal stem cell therapy (MSCT) is an experimental stem cell therapy currently undergoing clinical trials. Animal models and early clinical trials have shown promise that MSCT might be a low risk treatment to precipitate neuroregeneration and immunomodulation in MS patients. Specifically, neuroprogenitor and placental-derived mesenchymal stem cells offer the best hope for a practical treatment for MS. Stem cell therapy, and perhaps a combinatorial therapeutic approach, holds promise for a better treatment for MS. PMID:23862098

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

PubMed

Calabrese, Massimiliano; Gajofatto, Alberto; Gobbin, Francesca; Turri, Giulia; Richelli, Silvia; Matinella, Angela; Oliboni, Eugenio Simone; Benedetti, Maria Donata; Monaco, Salvatore

2015-04-01

Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs. © The Author(s), 2014.

40 CFR Appendix A to Part 58 - Quality Assurance Requirements for SLAMS, SPMs and PSD Air Monitoring

Code of Federal Regulations, 2014 CFR

2014-07-01

... monitor. 3.3.4.4Pb Performance Evaluation Program (PEP) Procedures. Each year, one performance evaluation... Information 2. Quality System Requirements 3. Measurement Quality Check Requirements 4. Calculations for Data... 10 of this appendix) and at a national level in references 1, 2, and 3 of this appendix. 1...

40 CFR Appendix A to Part 58 - Quality Assurance Requirements for SLAMS, SPMs and PSD Air Monitoring

Code of Federal Regulations, 2013 CFR

2013-07-01

... monitor. 3.3.4.4Pb Performance Evaluation Program (PEP) Procedures. Each year, one performance evaluation... Information 2. Quality System Requirements 3. Measurement Quality Check Requirements 4. Calculations for Data... 10 of this appendix) and at a national level in references 1, 2, and 3 of this appendix. 1...

Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease

PubMed Central

Germi, Raphaëlle; Bernard, Corinne; Garcia-Montojo, Marta; Deluen, Cécile; Farinelli, Laurent; Faucard, Raphaël; Veas, Francisco; Stefas, Ilias; Fabriek, Babs O; Van-Horssen, Jack; Van-der-Valk, Paul; Gerdil, Claire; Mancuso, Roberta; Saresella, Marina; Clerici, Mario; Marcel, Sébastien; Creange, Alain; Cavaretta, Rosella; Caputo, Domenico; Arru, Giannina; Morand, Patrice; Lang, Alois B; Sotgiu, Stefano; Ruprecht, Klemens; Rieckmann, Peter; Villoslada, Pablo; Chofflon, Michel; Boucraut, Jose; Pelletier, Jean; Hartung, Hans-Peter

2012-01-01

Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family ‘W’ (HERV-W), induces dysimmunity and inflammation. Objective: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. Methods: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. Results: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing–remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS –<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements. PMID:22457345

Is physical exercise a multiple sclerosis disease modifying treatment?

PubMed

Motl, Robert W; Pilutti, Lara A

2016-08-01

There is consensus that exercise represents a behavioral approach for the restoration of function and management of symptoms among persons with multiple sclerosis (MS). The current paper provides a review on the topic of exercise and physical activity as MS-disease modifying treatments. Firstly, metrics for evaluating disease modification and progression in MS are described. Secondly, evidence for exercise as a MS-disease modifying therapy based on individual studies, literature reviews, and meta-analyses is summarized. Finally, the paper focuses on major limitations of the existing body of research. Expert commentary: Exercise and physical activity have been associated with reduced relapse rate, mobility disability and its progression, and lesion volume, and improved neuroperformance, particularly walking outcomes. This evidence provides a positive, yet preliminary, picture for exercise having possible effects on markers of disease modification and progression in MS.

Comparison of Standard Automated Perimetry, Short-Wavelength Automated Perimetry, and Frequency-Doubling Technology Perimetry to Monitor Glaucoma Progression

PubMed Central

Hu, Rongrong; Wang, Chenkun; Gu, Yangshun; Racette, Lyne

2016-01-01

Abstract Detection of progression is paramount to the clinical management of glaucoma. Our goal is to compare the performance of standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry in monitoring glaucoma progression. Longitudinal data of paired SAP, SWAP, and FDT from 113 eyes with primary open-angle glaucoma enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. Data from all tests were expressed in comparable units by converting the sensitivity from decibels to unitless contrast sensitivity and by expressing sensitivity values in percent of mean normal based on an independent dataset of 207 healthy eyes with aging deterioration taken into consideration. Pointwise linear regression analysis was performed and 3 criteria (conservative, moderate, and liberal) were used to define progression and improvement. Global mean sensitivity (MS) was fitted with linear mixed models. No statistically significant difference in the proportion of progressing and improving eyes was observed across tests using the conservative criterion. Fewer eyes showed improvement on SAP compared to SWAP and FDT using the moderate criterion; and FDT detected less progressing eyes than SAP and SWAP using the liberal criterion. The agreement between these test types was poor. The linear mixed model showed a progressing trend of global MS overtime for SAP and SWAP, but not for FDT. The baseline estimate of SWAP MS was significantly lower than SAP MS by 21.59% of mean normal. FDT showed comparable estimation of baseline MS with SAP. SWAP and FDT do not appear to have significant benefits over SAP in monitoring glaucoma progression. SAP, SWAP, and FDT may, however, detect progression in different glaucoma eyes. PMID:26886602

Primary-Progressive MS (PPMS)

MedlinePlus

... Disease T Cells d What Causes MS? Disproved Theories Viruses Clusters d Who Gets MS? Pediatric MS ... of Distinction Lawry Circle Circle of Influence d Planned Giving d Other Ways to Give Donate by ...

Progressive-Relapsing MS (PRMS)

MedlinePlus

... Disease T Cells d What Causes MS? Disproved Theories Viruses Clusters d Who Gets MS? Pediatric MS ... of Distinction Lawry Circle Circle of Influence d Planned Giving d Other Ways to Give Donate by ...

Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS).

PubMed

Glatigny, Simon; Bettelli, Estelle

2018-01-08

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons. It can present with variable clinical and pathological manifestations, which might reflect the involvement of distinct pathogenic processes. Although the mechanisms leading to the development of the disease are not fully understood, numerous evidences indicate that MS is an autoimmune disease, the initiation and progression of which are dependent on an autoimmune response against myelin antigens. In addition, genetic susceptibility and environmental triggers likely contribute to the initiation of the disease. At this time, there is no cure for MS, but several disease-modifying therapies (DMTs) are available to control and slow down disease progression. A good number of these DMTs were identified and tested using animal models of MS referred to as experimental autoimmune encephalomyelitis (EAE). In this review, we will recapitulate the characteristics of EAE models and discuss how they help shed light on MS pathogenesis and help test new treatments for MS patients. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Exercise Training in Progressive Multiple Sclerosis: A Comparison of Recumbent Stepping and Body Weight-Supported Treadmill Training.

PubMed

Pilutti, Lara A; Paulseth, John E; Dove, Carin; Jiang, Shucui; Rathbone, Michel P; Hicks, Audrey L

2016-01-01

Background: There is evidence of the benefits of exercise training in multiple sclerosis (MS); however, few studies have been conducted in individuals with progressive MS and severe mobility impairment. A potential exercise rehabilitation approach is total-body recumbent stepper training (TBRST). We evaluated the safety and participant-reported experience of TBRST in people with progressive MS and compared the efficacy of TBRST with that of body weight-supported treadmill training (BWSTT) on outcomes of function, fatigue, and health-related quality of life (HRQOL). Methods: Twelve participants with progressive MS (Expanded Disability Status Scale scores, 6.0-8.0) were randomized to receive TBRST or BWSTT. Participants completed three weekly sessions (30 minutes) of exercise training for 12 weeks. Primary outcomes included safety assessed as adverse events and patient-reported exercise experience assessed as postexercise response and evaluation of exercise equipment. Secondary outcomes included the Multiple Sclerosis Functional Composite, the Modified Fatigue Impact Scale, and the Multiple Sclerosis Quality of Life-54 questionnaire scores. Assessments were conducted at baseline and after 12 weeks. Results: Safety was confirmed in both exercise groups. Participants reported enjoying both exercise modalities; however, TBRST was reviewed more favorably. Both interventions reduced fatigue and improved HRQOL (P ≤ .05); there were no changes in function. Conclusions: Both TBRST and BWSTT seem to be safe, well tolerated, and enjoyable for participants with progressive MS with severe disability. Both interventions may also be efficacious for reducing fatigue and improving HRQOL. TBRST should be further explored as an exercise rehabilitation tool for patients with progressive MS.

Walking impairment in patients with multiple sclerosis: exercise training as a treatment option.

PubMed

Motl, Robert W; Goldman, Myla D; Benedict, Ralph H B

2010-11-16

Multiple sclerosis (MS) is a chronic disease of the central nervous system that culminates in the progression of physical and cognitive disability over time. Walking impairment is a ubiquitous feature of MS and a sentinel characteristic of the later or advanced stages of the disease. This paper presents a conceptual rationale along with empirical evidence for exercise training as a rehabilitation approach for managing walking impairment and improving walking function in persons with MS. Conceptually, MS is associated with a decrease in physical activity, which, in turn, can result in deconditioning across multiple domains of physiological functioning. The resulting deconditioning feeds back and further drives physical inactivity until a threshold is reached that likely initiates the progression of walking impairment in MS. Empirically, physical activity and exercise training have been associated with beneficial effects on walking function in persons with MS. This is based on cross-sectional, longitudinal, and experimental research that included diversity in the breadth of measures of walking, persons with MS, and exercise/physical activity characteristics. Of particular importance, future researchers might consider examining the combinatory effects of exercise training plus pharmacological agents on walking mobility in MS. Collectively, exercise training and physical activity might hold significant potential for the management of progressive mobility disability in MS.

Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage.

PubMed

Morel, Agnieszka; Bijak, Michał; Miller, Elżbieta; Rywaniak, Joanna; Miller, Sergiusz; Saluk, Joanna

2015-01-01

Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of O2 (-∙) in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets.

Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage

PubMed Central

Bijak, Michał; Miller, Elżbieta; Miller, Sergiusz

2015-01-01

Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of O2 −∙ in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets. PMID:26064417

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

PubMed

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model.

PubMed

Bogosian, Angeliki; Morgan, Myfanwy; Bishop, Felicity L; Day, Fern; Moss-Morris, Rona

2017-03-01

We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment.

Imaging outcome measures for progressive multiple sclerosis trials

PubMed Central

Moccia, Marcello; de Stefano, Nicola; Barkhof, Frederik

2017-01-01

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation. PMID:29041865

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.

PubMed

Briken, S; Gold, S M; Patra, S; Vettorazzi, E; Harbs, D; Tallner, A; Ketels, G; Schulz, K H; Heesen, C

2014-03-01

Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. ISRCTN (trial number 76467492) http://isrctn.org.

High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

PubMed

Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

2015-03-01

No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Characterization of naïve, memory and effector T cells in progressive multiple sclerosis.

PubMed

Nielsen, Birgitte Romme; Ratzer, Rikke; Börnsen, Lars; von Essen, Marina Rode; Christensen, Jeppe Romme; Sellebjerg, Finn

2017-09-15

We characterized naïve, central memory (CM), effector memory (EM) and terminally differentiated effector memory (TEMRA) CD4 + and CD8 + T cells and their expression of CD49d and CD26 in peripheral blood in patients with multiple sclerosis (MS) and healthy controls. CD26 + CD28 + CD4 + TEMRA T cells were increased in all subtypes of MS, and CD26 + CD28 + CD8 + TEMRA T cells were increased in relapsing-remitting and secondary progressive MS. Conversely, in progressive MS, CD49d + CM T cells were decreased and natalizumab increased the circulating number of all six subsets but reduced the frequency of most subsets expressing CD49d and CD26. Copyright © 2017 Elsevier B.V. All rights reserved.

How does work disability of patients with MS develop before and after diagnosis? A nationwide cohort study with a reference group.

PubMed

Gyllensten, Hanna; Wiberg, Michael; Alexanderson, Kristina; Hillert, Jan; Tinghög, Petter

2016-11-17

We compared work disability of patients with multiple sclerosis (MS) from 5 years before with 5 years after diagnosis, with that of matched controls, and analysed whether progression in work disability among patients with MS was associated with sociodemography. Population-based cohort study. The adult Swedish general population. Residents aged 24-57 diagnosed with MS (n=3685) in 2003-2006 and 18 425 matched controls without MS. Annual net days of sickness absence (SA) and disability pension (DP), used as a proxy for work disability, followed from 5 years before to 5 years after diagnosis (ie, T-5-T+5). For patients with MS, regression was used to identify sociodemographic factors related to progression in work disability. Work disability of patients with MS increased gradually between T-5 and T-1 (mean: 46-82 days) followed by a sharp increase (T+1, 142 days), after which only a marginal increase was observed (T+5, 149 days). The matched controls had less work disability, slightly increasing during the period to a maximum of ∼40 days. Men with MS had a sharper increase in work disability before diagnosis. High educational level was associated with less progression in work disability before and around diagnosis. Patients with MS had more work disability days also 5 years before diagnosis. Several sociodemographic variables were associated with the absolute level and the progression in SA and DP. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Delayed P100-Like Latencies in Multiple Sclerosis: A Preliminary Investigation Using Visual Evoked Spread Spectrum Analysis

PubMed Central

Kiiski, Hanni S. M.; Ní Riada, Sinéad; Lalor, Edmund C.; Gonçalves, Nuno R.; Nolan, Hugh; Whelan, Robert; Lonergan, Róisín; Kelly, Siobhán; O'Brien, Marie Claire; Kinsella, Katie; Bramham, Jessica; Burke, Teresa; Ó Donnchadha, Seán; Hutchinson, Michael; Tubridy, Niall; Reilly, Richard B.

2016-01-01

Conduction along the optic nerve is often slowed in multiple sclerosis (MS). This is typically assessed by measuring the latency of the P100 component of the Visual Evoked Potential (VEP) using electroencephalography. The Visual Evoked Spread Spectrum Analysis (VESPA) method, which involves modulating the contrast of a continuous visual stimulus over time, can produce a visually evoked response analogous to the P100 but with a higher signal-to-noise ratio and potentially higher sensitivity to individual differences in comparison to the VEP. The main objective of the study was to conduct a preliminary investigation into the utility of the VESPA method for probing and monitoring visual dysfunction in multiple sclerosis. The latencies and amplitudes of the P100-like VESPA component were compared between healthy controls and multiple sclerosis patients, and multiple sclerosis subgroups. The P100-like VESPA component activations were examined at baseline and over a 3-year period. The study included 43 multiple sclerosis patients (23 relapsing-remitting MS, 20 secondary-progressive MS) and 42 healthy controls who completed the VESPA at baseline. The follow-up sessions were conducted 12 months after baseline with 24 MS patients (15 relapsing-remitting MS, 9 secondary-progressive MS) and 23 controls, and again at 24 months post-baseline with 19 MS patients (13 relapsing-remitting MS, 6 secondary-progressive MS) and 14 controls. The results showed P100-like VESPA latencies to be delayed in multiple sclerosis compared to healthy controls over the 24-month period. Secondary-progressive MS patients had most pronounced delay in P100-like VESPA latency relative to relapsing-remitting MS and controls. There were no longitudinal P100-like VESPA response differences. These findings suggest that the VESPA method is a reproducible electrophysiological method that may have potential utility in the assessment of visual dysfunction in multiple sclerosis. PMID:26726800

The development of an MRI lesion quantifying system for multiple sclerosis patients undergoing treatment

NASA Astrophysics Data System (ADS)

Moin, Paymann; Ma, Kevin; Amezcua, Lilyana; Gertych, Arkadiusz; Liu, Brent

2009-02-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that affects approximately 2.5 million people worldwide. Magnetic resonance imaging (MRI) is an established tool for the assessment of disease activity, progression and response to treatment. The progression of the disease is variable and requires routine follow-up imaging studies. Currently, MRI quantification of multiple sclerosis requires a manual approach to lesion measurement and yields an estimate of lesion volume and interval change. In the setting of several prior studies and a long treatment history, trends related to treatment change quickly become difficult to extrapolate. Our efforts seek to develop an imaging informatics based MS lesion computer aided detection (CAD) package to quantify and track MS lesions including lesion load, volume, and location. Together, with select clinical parameters, this data will be incorporated into an MS specific e- Folder to provide decision support to evaluate and assess treatment options for MS in a manner tailored specifically to an individual based on trends in MS presentation and progression.

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

PubMed Central

Tejera-Alhambra, Marta; Casrouge, Armanda; de Andrés, Clara; Seyfferth, Ansgar; Ramos-Medina, Rocío; Alonso, Bárbara; Vega, Janet; Fernández-Paredes, Lidia; Albert, Matthew L.; Sánchez-Ramón, Silvia

2015-01-01

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients. PMID:26039252

The topographical model of multiple sclerosis

PubMed Central

Cook, Karin; De Nino, Scott; Fletcher, Madhuri

2016-01-01

Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested. PMID:27648465

40 CFR Appendix A to Part 58 - Quality Assurance Requirements for SLAMS, SPMs and PSD Air Monitoring

Code of Federal Regulations, 2011 CFR

2011-07-01

... in section 4.3.1 of this appendix. 3.2.7PM2.5 Performance Evaluation Program (PEP) Procedures. The... evaluation audit means that both the primary monitor and PEP audit concentrations are valid and above 3 µg/m3... Evaluation Program (PEP) Procedures. Each year, one performance evaluation audit, as described in section 3.2...

40 CFR Appendix A to Part 58 - Quality Assurance Requirements for SLAMS, SPMs and PSD Air Monitoring

Code of Federal Regulations, 2012 CFR

2012-07-01

... in section 4.3.1 of this appendix. 3.2.7PM2.5 Performance Evaluation Program (PEP) Procedures. The... evaluation audit means that both the primary monitor and PEP audit concentrations are valid and above 3 µg/m3... Evaluation Program (PEP) Procedures. Each year, one performance evaluation audit, as described in section 3.2...

For a Limited Time Only? How Long Can Trees Maintain Enhanced Chemical Defenses During Pre-Mortality Heat and Drought Stress

NASA Astrophysics Data System (ADS)

Trowbridge, A.; Adams, H. D.; Cook, A. A.; Hofland, M.; Weaver, D.; McDowell, N. G.

2016-12-01

The relative contribution of forest pests to climate and drought-induced tree mortality is complex and largely absent from current process-based models. Recent efforts have focused on developing frameworks to integrate insects into models of tree mortality, citing the need for a better mechanistic understanding of the links between stress-induced tree physiology and insect behavior and population dynamics. Secondary plant metabolites (SPMs) play a critical role in plant resistance and their synthesis and mobilization are coupled to carbon assimilation, hydraulic conductivity, and herbivory itself. Insect host choice also depends in part on behavioral responses to host SPMs. Monoterpenes are the dominant SPMs in conifers, and while high concentrations of monoterpenes are toxic to bark beetles, lower concentrations serve as precursors for a number of aggregation pheromones. Thus, the impact of monoterpenes on bark beetle behavior is complex and is impacted by environmental effects on primary metabolism including heat and drought stress. Here, we quantify the dynamics of piñon pine monoterpene chemistry as a function of predicted and prolonged drought stress implemented at the SUrvival MOrtality (SUMO) experimental site at the Los Alamos National Laboratory, NM, USA. In both woody and needle tissues, total monoterpene concentrations in ambient trees were not significantly different from those observed in trees exposed to heat stress, but drought trees showed higher total concentration while heat+drought trees were observed to have the highest levels (2 fold increase over ambient). These treatment effects were sustained over a two-year period despite seasonal variation in tree water status; however, total concentration in the xylem and phloem were closely coupled to tree water potential and treatment effects took longer to manifest relative to the needles. Individual compounds responded differently to the treatments, suggesting cyclase-level enzyme regulation, while α-pinene - an important bark beetle aggregate pheromone precursor - dominated total monoterpene concentration dynamics. These results have important implications for piñon-bark beetle interactions during drought and provide a missing link between drought-induced physiology and insect behavior.

Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis.

PubMed

Eickmeier, Olaf; Fussbroich, Daniela; Mueller, Klaus; Serve, Friederike; Smaczny, Christina; Zielen, Stefan; Schubert, Ralf

2017-01-01

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF. In this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach. DHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05). SPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was present in sputum and plasma of CF patients and may serve as a representative peripheral biomarker of the lung resolution program for CF patients.

Progressive solitary sclerosis

PubMed Central

Kaufmann, Timothy J.; Weinshenker, Brian G.; Kantarci, Orhun H.; Schmalstieg, William F.; Paz Soldan, M. Mateo; Flanagan, Eoin P.

2016-01-01

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. Results: The patients' median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. PMID:27638926

Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

PubMed

Pryce, Gareth; Baker, David

2015-01-01

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

Imbalance in Fatty-Acid-Chain Length of Gangliosides Triggers Alzheimer Amyloid Deposition in the Precuneus

PubMed Central

Oikawa, Naoto; Matsubara, Teruhiko; Fukuda, Ryoto; Yasumori, Hanaki; Hatsuta, Hiroyuki; Murayama, Shigeo; Sato, Toshinori; Suzuki, Akemi; Yanagisawa, Katsuhiko

2015-01-01

Amyloid deposition, a crucial event of Alzheimer’s disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition. PMID:25798597

Double image encryption in Fresnel domain using wavelet transform, gyrator transform and spiral phase masks

NASA Astrophysics Data System (ADS)

Kumar, Ravi; Bhaduri, Basanta

2017-06-01

In this paper, we propose a new technique for double image encryption in the Fresnel domain using wavelet transform (WT), gyrator transform (GT) and spiral phase masks (SPMs). The two input mages are first phase encoded and each of them are then multiplied with SPMs and Fresnel propagated with distances d1 and d2, respectively. The single-level discrete WT is applied to Fresnel propagated complex images to decompose each into sub-band matrices i.e. LL, HL, LH and HH. Further, the sub-band matrices of two complex images are interchanged after modulation with random phase masks (RPMs) and subjected to inverse discrete WT. The resulting images are then both added and subtracted to get intermediate images which are further Fresnel propagated with distances d3 and d4, respectively. These outputs are finally gyrator transformed with the same angle α to get the encrypted images. The proposed technique provides enhanced security in terms of a large set of security keys. The sensitivity of security keys such as SPM parameters, GT angle α, Fresnel propagation distances are investigated. The robustness of the proposed techniques against noise and occlusion attacks are also analysed. The numerical simulation results are shown in support of the validity and effectiveness of the proposed technique.

Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE-/- Mice.

PubMed

Gonzalez, Jaime; Donoso, Wendy; Sandoval, Nathalie; Reyes, María; Gonzalez, Priscila; Gajardo, Monica; Morales, Erik; Neira, Amalia; Razmilic, Iván; Yuri, José A; Moore-Carrasco, Rodrigo

2015-01-01

Cardiovascular Diseases (CVD) represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS). It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE-/- mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA)) of MS model in CF1 mice significantly. The model apoE-/- mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice.

Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

PubMed Central

Gonzalez, Jaime; Donoso, Wendy; Sandoval, Nathalie; Reyes, María; Gonzalez, Priscila; Gajardo, Monica; Morales, Erik; Neira, Amalia; Razmilic, Iván; Yuri, José A.

2015-01-01

Cardiovascular Diseases (CVD) represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS). It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE−/− mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA)) of MS model in CF1 mice significantly. The model apoE−/− mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice. PMID:26075004

Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.

PubMed

Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P

2016-10-18

To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.

Reduced rich-club connectivity is related to disability in primary progressive MS

PubMed Central

Hodecker, Sibylle; Cheng, Bastian; Wanke, Nadine; Young, Kim Lea; Hilgetag, Claus; Gerloff, Christian; Heesen, Christoph; Thomalla, Götz; Siemonsen, Susanne

2017-01-01

Objective: To investigate whether the structural connectivity of the brain's rich-club organization is altered in patients with primary progressive MS and whether such changes to this fundamental network feature are associated with disability measures. Methods: We recruited 37 patients with primary progressive MS and 21 healthy controls for an observational cohort study. Structural connectomes were reconstructed based on diffusion-weighted imaging data using probabilistic tractography and analyzed with graph theory. Results: We observed the same topological organization of brain networks in patients and controls. Consistent with the originally defined rich-club regions, we identified superior frontal, precuneus, superior parietal, and insular cortex in both hemispheres as rich-club nodes. Connectivity within the rich club was significantly reduced in patients with MS (p = 0.039). The extent of reduced rich-club connectivity correlated with clinical measurements of mobility (Kendall rank correlation coefficient τ = −0.20, p = 0.047), hand function (τ = −0.26, p = 0.014), and information processing speed (τ = −0.20, p = 0.049). Conclusions: In patients with primary progressive MS, the fundamental organization of the structural connectome in rich-club and peripheral nodes was preserved and did not differ from healthy controls. The proportion of rich-club connections was altered and correlated with disability measures. Thus, the rich-club organization of the brain may be a promising network phenotype for understanding the patterns and mechanisms of neurodegeneration in MS. PMID:28804744

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

PubMed

Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Atrophied Brain Lesion Volume: A New Imaging Biomarker in Multiple Sclerosis.

PubMed

Dwyer, Michael G; Bergsland, Niels; Ramasamy, Deepa P; Jakimovski, Dejan; Weinstock-Guttman, Bianca; Zivadinov, Robert

2018-06-01

Lesion accrual in multiple sclerosis (MS) is an important and clinically relevant measure, used extensively as an imaging trial endpoint. However, lesions may also shrink or disappear entirely due to atrophy. Although generally ignored or treated as a nuisance, this phenomenon may actually be an important stand-alone imaging biomarker. Therefore, we investigated the rate of brain lesion loss due to atrophy (atrophied lesion volume) in MS subtypes compared to baseline lesion volume and to new and enlarging lesion volumes, and evaluated the independent predictive value of this phenomenon for clinical disability. A total of 192 patients (18 clinically isolated syndrome, 126 relapsing-remitting MS, and 48 progressive) received 3T magnetic resonance imaging at baseline and 5 years. Lesions were quantified at baseline, and new/enlarging lesion volumes were calculated over the study interval. Atrophied lesion volume was calculated by combining baseline lesion masks with follow-up SIENAX-derived cerebrospinal fluid partial volume maps. Measures were compared between disease subgroups, and correlations with disability change (Expanded Disability Status Scale [EDSS]) were evaluated. Hierarchical regression was employed to determine the unique additive value of atrophied lesion volume. Atrophied lesion volume was different between MS subtypes (P = .02), and exceeded new lesion volume accumulation in progressive MS (298.1 vs. 75.5 mm 3 ). Atrophied lesion volume was the only significant correlate of EDSS change (r = .192 relapsing, r = .317 progressive, P < .05), and explained significant additional variance when controlling for brain atrophy and new/enlarging lesion volume (R 2 .092 vs. .045, P = .003). Atrophied lesion volume is a unique and clinically relevant imaging marker in MS, with particular promise in progressive MS. Copyright © 2018 by the American Society of Neuroimaging.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

PubMed

Rae-Grant, Alexander; Day, Gregory S; Marrie, Ruth Ann; Rabinstein, Alejandro; Cree, Bruce A C; Gronseth, Gary S; Haboubi, Michael; Halper, June; Hosey, Jonathan P; Jones, David E; Lisak, Robert; Pelletier, Daniel; Potrebic, Sonja; Sitcov, Cynthia; Sommers, Rick; Stachowiak, Julie; Getchius, Thomas S D; Merillat, Shannon A; Pringsheim, Tamara

2018-04-24

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers. © 2018 American Academy of Neurology.

"Cure" for multiple sclerosis (MS)-Evolving views of therapy goals in patients on different stages of the disease: A pilot study in a cohort of Polish MS patients.

PubMed

Chacińska, Weronika; Brzostowska, Marta; Nojszewska, Monika; Podlecka-Piętowska, Aleksandra; Jędrzejczak, Wiesław W; Snarski, Emilian

2017-06-01

New aggressive treatments promise improvement of results in the treatment of multiple sclerosis (MS), however, with high risk of serious complications. In this study, we analyzed patients' acceptance for risks connected with the MS treatment. The study was designed as a prospective nonanonymous online questionnaire. Responders were asked about the definition of the "cure" for MS and crucial goals in the treatment. One hundred and eighty patients filled in the questionnaire (129 women and 51 men), and the mean age was 33 years ( SD  = 10.29). The MS forms were as follows: relapsing-remitting (65%), secondary progressive (14%), primary progressive (10%), and other (11%), with mean EDSS score of 3 points ( SD  = 2.6). For 50% of the patients, relief of symptoms such as fatigue (72%), paresis (66%), and balance disorders (65%) was synonymous with "cure." The patients with faster progression of the disease were likely to accept risky "curative" treatments-with average 68% accepted mortality risk ( p  = .003). Over 81% of patients accepted mortality rates over 1% for the treatment that achieves self-defined cure. The study shows that the MS patients are likely to accept even very risky treatments as long as they promise patient-defined "cure."

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro.

PubMed

Redondo, Juliana; Sarkar, Pamela; Kemp, Kevin; Virgo, Paul F; Pawade, Joya; Norton, Aimie; Emery, David C; Guttridge, Martin G; Marks, David I; Wilkins, Alastair; Scolding, Neil J; Rice, Claire M

2017-05-01

Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by the Medical Research Council, UK (grant no. MR/K004166/1). The ACTiMuS study is sup-ported by the Silverman Family Foundation, Multiple Sclerosis Trust, Rosetree’s Trust, Catholic Bishops of England and Wales and Friends of Frenchay and SIAMMS-II by the Sir Halley Stewart Trust. C.M.R., P.S., and K.K. received support from the Burden Neurological Institute.

Prevalence of Walking-Related Motor Fatigue in Persons With Multiple Sclerosis: Decline in Walking Distance Induced by the 6-Minute Walk Test.

PubMed

Leone, Carmela; Severijns, Deborah; Doležalová, Vendula; Baert, Ilse; Dalgas, Ulrik; Romberg, Anders; Bethoux, Francois; Gebara, Benoit; Santoyo Medina, Carmen; Maamâgi, Heigo; Rasova, Kamila; Maertens de Noordhout, Benoît; Knuts, Kathy; Skjerbaek, Anders; Jensen, Ellen; Wagner, Joanne M; Feys, Peter

2016-05-01

To investigate the individual occurrence of walking-related motor fatigue in persons with multiple sclerosis (PwMS), according to disability level and disease phenotype.Study design This was a cross-sectional, multinational study.Participants They were 208 PwMS from 11 centers with Expanded Disability Status Scale (EDSS) scores up to 6.5. The percentage change in distance walked (distance walked index, DWI) was calculated between minute 6 and 1 (DWI(6-1)) of the 6-Minute Walk Test (6MWT). Its magnitude was used to classify participants into 4 subgroups: (1) DWI(6-1)[≥5%], (2) DWI(6-1)[5%; -5%], (3) DWI(6-1)[-5%; > -15%], and (4) DWI(6-1)[≤-15%]. The latter group was labeled as having walking-related motor fatigue. PwMS were stratified into 5 subgroups based on the EDSS (0-2.5, 3-4, 4.5-5.5, 6, 6.5) and 3 subgroups based on MS phenotype (relapsing remitting [RR], primary progressive [PP], and secondary progressive [SP]). The DWI6-1was ≥5% in 16 PwMS (7.7%), between 5% and -5% in 70 PwMS (33.6%), between -5% and -15% in 58 PwMS (24%), and ≤-15% in 64 PwMS (30.8%). The prevalence of walking-related motor fatigue (DWI(6-1)[≤-15%]) was significantly higher among the progressive phenotype (PP = 50% and SP = 39%; RR = 15.6%) and PwMS with higher disability level (EDSS 4.5-5.5 = 48.3%, 6 = 46.3% and 6.5 = 51.5%, compared with EDSS 0-2.5 = 7.8% and 3-4 = 16.7%;P< .05). Stepwise multiple regression analysis indicated that EDSS, but not MS phenotype, explained a significant part of the variance in DWI(6-1)(R(2)= 0.086;P< .001). More than one-third of PwMS showed walking-related motor fatigue during the 6MWT, with its prevalence greatest in more disabled persons (up to 51%) and in those with progressive MS phenotype (up to 50%). Identification of walking-related motor fatigue may lead to better-tailored interventions. © The Author(s) 2015.

Distributional Monte Carlo Methods for the Boltzmann Equation

DTIC Science & Technology

2013-03-01

Presented to the Faculty Graduate School of Engineering and Management Air Force Institute of Technology Air University Air Education and Training Command...Interim Dean, Graduate School of Engineering and Management 8 Mar 2013 Date AFIT-ENC-DS-13-M-06 Abstract Stochastic particle methods (SPMs) for the...applied to the well-studied Bobylev-Krook-Wu solution as a numerical test case. Accuracy and variance of the solutions are examined as functions of various

Progressive multiple sclerosis, cognitive function, and quality of life.

PubMed

Højsgaard Chow, Helene; Schreiber, Karen; Magyari, Melinda; Ammitzbøll, Cecilie; Börnsen, Lars; Romme Christensen, Jeppe; Ratzer, Rikke; Soelberg Sørensen, Per; Sellebjerg, Finn

2018-02-01

Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS. This is a retrospective study of 52 patients with primary progressive ( N  = 18) and secondary progressive MS ( N  = 34). Physical disability was assessed using the Expanded Disability Status Scale, Timed 25 Foot Walk (T25FW) test and 9-Hole Peg Test (9HPT). Cognitive function was assessed using Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test, and Trail Making Test B (TRAIL-B). In addition, quality of life was assessed by the Short Form 36 (SF-36) questionnaire. Only measures of cognitive function correlated with the overall SF-36 quality of life score and the Mental Component Summary score from the SF-36. The only physical measure that correlated with a measure of quality of life was T25FW test, which correlated with the Physical Component Summary from the SF-36. We found no other significant correlations between the measures of cognitive function and the overall physical measures but interestingly, we found a possible relationship between the 9HPT score for the nondominant hand and the SDMT and TRAIL-B. Our findings support inclusion of measures of cognitive function in the assessment of patients with progressive MS as these correlated closer with quality of life than measures of physical impairment.

Visual field impairment captures disease burden in multiple sclerosis.

PubMed

Ortiz-Perez, Santiago; Andorra, Magí; Sanchez-Dalmau, Bernardo; Torres-Torres, Rubén; Calbet, David; Lampert, Erika J; Alba-Arbalat, Salut; Guerrero-Zamora, Ana M; Zubizarreta, Irati; Sola-Valls, Nuria; Llufriu, Sara; Sepúlveda, María; Saiz, Albert; Villoslada, Pablo; Martinez-Lapiscina, Elena H

2016-04-01

Monitoring disease burden is an unmeet need in multiple sclerosis (MS). Identifying patients at high risk of disability progression will be useful for improving clinical-therapeutic decisions in clinical routine. To evaluate the role of visual field testing in non-optic neuritis eyes (non-ON eyes) as a biomarker of disability progression in MS. In 109 patients of the MS-VisualPath cohort, we evaluated the association between visual field abnormalities and global and cognitive disability markers and brain and retinal imaging markers of neuroaxonal injury using linear regression models adjusted for sex, age, disease duration and use of disease-modifying therapies. We evaluated the risk of disability progression associated to have baseline impaired visual field after 3 years of follow-up. Sixty-two percent of patients showed visual field defects in non-ON eyes. Visual field mean deviation was statistically associated with global disability; brain (normalized brain parenchymal, gray matter volume and lesion load) and retinal (peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex thickness) markers of neuroaxonal damage. Patients with impaired visual field had statistically significative greater disability, lower normalized brain parenchymal volume and higher lesion volume than patients with normal visual field testing. MS patients with baseline impaired VF tripled the risk of disability progression during follow-up [OR = 3.35; 95 % CI (1.10-10.19); p = 0.033]. The association of visual field impairment with greater disability and neuroaxonal injury and higher risk of disability progression suggest that VF could be used to monitor MS disease burden.

MIF functional polymorphisms (-794 CATT5-8 and -173 G>C) are associated with MIF serum levels, severity and progression in male multiple sclerosis from western Mexican population.

PubMed

Castañeda-Moreno, V A; De la Cruz-Mosso, U; Torres-Carrillo, N; Macías-Islas, M A; Padilla-De la Torre, O; Mireles-Ramírez, M A; González-Pérez, O; Ruiz-Sandoval, J L; Huerta, M; Trujillo, X; Ortuño-Sahagún, D; Muñoz-Valle, J F

2018-07-15

Macrophage migration inhibitory factor (MIF) is a cytokine associated with tissue damage in multiple autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis. The role of MIF in multiple sclerosis (MS) and the contribution of its polymorphisms are unknown in our population. Therefore, we decided to investigate the genetic association of -794 CATT 5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms with MS, clinical variables and MIF serum levels in the population of western Mexico. 230 MS patients diagnosed according to McDonald criteria and 248 control subjects (CS) were recruited for this study, both polymorphisms were genotyped by PCR and PCR-RFLP and MIF serum levels were measured by ELISA kit. Severity and progression of MS were evaluated by EDSS and MSSS scores, respectively. Genotypes carrying the 5 repeats alleles of -794 CATT 5-8 MIF polymorphism present higher MIF serum levels in comparison with no carriers, and the presence of 5,7 heterozygous genotype contribute to the increase of disease severity and damage progression in MS patients. Notably when we stratified by sex, an effect of risk alleles (7 repeats and -173*C) of both MIF polymorphisms on EDSS and MSSS scores on males was found (p < 0.01). This study suggests that polymorphic alleles of MIF polymorphisms could act as sex-specific disease modifiers that increase the severity and progression of MS in male Mexican-Mestizo western population. Copyright © 2018 Elsevier B.V. All rights reserved.

Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE

PubMed Central

Radbruch, Helena; Bremer, Daniel; Guenther, Robert; Cseresnyes, Zoltan; Lindquist, Randall; Hauser, Anja E.; Niesner, Raluca

2016-01-01

Most multiple sclerosis (MS) patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in MS is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic MS. Here, we employ intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1–4, DUOX1, 2) and, thus, to identify the cellular source of oxidative stress in the CNS of mice affected by experimental autoimmune encephalomyelitis (EAE) in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET–FLIM, providing a possible mechanism of disease progression in MS. PMID:27014271

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

PubMed

Ball, Susan; Vickery, Jane; Hobart, Jeremy; Wright, Dave; Green, Colin; Shearer, James; Nunn, Andrew; Cano, Mayam Gomez; MacManus, David; Miller, David; Mallik, Shahrukh; Zajicek, John

2015-02-01

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. Current Controlled Trials ISRCTN62942668. The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Quantitative measures detect sensory and motor impairments in multiple sclerosis.

PubMed

Newsome, Scott D; Wang, Joseph I; Kang, Jonathan Y; Calabresi, Peter A; Zackowski, Kathleen M

2011-06-15

Sensory and motor dysfunction in multiple sclerosis (MS) is often assessed with rating scales which rely heavily on clinical judgment. Quantitative devices may be more precise than rating scales. To quantify lower extremity sensorimotor measures in individuals with MS, evaluate the extent to which they can detect functional systems impairments, and determine their relationship to global disability measures. We tested 145 MS subjects and 58 controls. Vibration thresholds were quantified using a Vibratron-II device. Strength was quantified by a hand-held dynamometer. We also recorded Expanded Disability Status Scale (EDSS) and Timed 25-Foot Walk (T25FW). t-tests and Wilcoxon-rank sum were used to compare group data. Spearman correlations were used to assess relationships between each measure. We also used a step-wise linear regression model to determine how much the quantitative measures explain the variance in the respective functional systems scores (FSS). EDSS scores ranged from 0-7.5, mean disease duration was 10.4 ± 9.6 years, and 66% were female. In relapsing-remitting MS, but not progressive MS, poorer vibration sensation correlated with a worse EDSS score, whereas progressive groups' ankle/hip strength changed significantly with EDSS progression. Interestingly, not only did sensorimotor measures significantly correlate with global disability measures (i.e., EDSS), but they had improved sensitivity, as they detected impairments in up to 32% of MS subjects with normal sensory and pyramidal FSS. Sensory and motor deficits in MS can be quantified using clinically accessible tools and distinguish differences among MS subtypes. We show that quantitative sensorimotor measures are more sensitive than FSS from the EDSS. These tools have the potential to be used as clinical outcome measures in practice and for future MS clinical trials of neurorehabilitative and neuroreparative interventions. Copyright © 2011 Elsevier B.V. All rights reserved.

Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis

PubMed Central

Gupta, Shashank; Utoft, Regine; Hasseldam, Henrik; Schmidt-Christensen, Anja; Hannibal, Tine Dahlbaek; Hansen, Lisbeth; Fransén-Pettersson, Nina; Agarwal-Gupta, Noopur; Rozell, Björn; Andersson, Åsa; Holmberg, Dan

2013-01-01

Multiple Sclerosis (MS) is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS). T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE) animal models for the disease. A technology for quantitative and 3 dimensional (3D) spatial assessment of inflammation in this and other CNS inflammatory conditions is much needed. Here we present a procedure for 3D spatial assessment and global quantification of the development of neuroinflammation based on Optical Projection Tomography (OPT). Applying this approach to the analysis of rodent models of MS, we provide global quantitative data of the major inflammatory component as a function of the clinical course. Our data demonstrates a strong correlation between the development and progression of neuroinflammation and clinical disease in several mouse and a rat model of MS refining the information regarding the spatial dynamics of the inflammatory component in EAE. This method provides a powerful tool to investigate the effect of environmental and genetic forces and for assessing the therapeutic effects of drug therapy in animal models of MS and other neuroinflammatory/neurodegenerative disorders. PMID:24124545

Online differentiation of mineral phase in aerosol particles by ion formation mechanism using a LAAP-TOF single-particle mass spectrometer

NASA Astrophysics Data System (ADS)

Marsden, Nicholas A.; Flynn, Michael J.; Allan, James D.; Coe, Hugh

2018-01-01

Mineralogy of silicate mineral dust has a strong influence on climate and ecosystems due to variation in physiochemical properties that result from differences in composition and crystal structure (mineral phase). Traditional offline methods of analysing mineral phase are labour intensive and the temporal resolution of the data is much longer than many atmospheric processes. Single-particle mass spectrometry (SPMS) is an established technique for the online size-resolved measurement of particle composition by laser desorption ionisation (LDI) followed by time-of-flight mass spectrometry (TOF-MS). Although non-quantitative, the technique is able to identify the presence of silicate minerals in airborne dust particles from markers of alkali metals and silicate molecular ions in the mass spectra. However, the differentiation of mineral phase in silicate particles by traditional mass spectral peak area measurements is not possible. This is because instrument function and matrix effects in the ionisation process result in variations in instrument response that are greater than the differences in composition between common mineral phases.In this study, we introduce a novel technique that enables the differentiation of mineral phase in silicate mineral particles by ion formation mechanism measured from subtle changes in ion arrival times at the TOF-MS detector. Using a combination of peak area and peak centroid measurements, we show that the arrangement of the interstitial alkali metals in the crystal structure, an important property in silicate mineralogy, influences the ion arrival times of elemental and molecular ion species in the negative ion mass spectra. A classification scheme is presented that allowed for the differentiation of illite-smectite, kaolinite and feldspar minerals on a single-particle basis. Online analysis of mineral dust aerosol generated from clay mineral standards produced mineral fractions that are in agreement with bulk measurements reported by traditional XRD (X-ray diffraction) analysis.

Georgetown University and Hampton University Prostate Cancer Undergraduate Fellowship Program

DTIC Science & Technology

2015-10-01

Tyanna Jones-Gray (Dr. Vicente Notario), Ms. Damara Miller (Dr. Eliot Rosen), Ms. Jasmine Hatcher-Moorman (Dr. MaryBeth Martin), and Mr. Isaiah Brown...undergraduate students: 1. The Hampton University undergraduates (Ms. Tyanna Jones-Gray, Ms. Damara Miller, Ms. Jasmine Hatcher-Moorman, and Mr...cancer progression. Dr. Martin’s lab has identified the environmental hormones referred to as metallo- hormones. In Dr. Martin’s laboratory, Jasmine

Physical activity and pediatric multiple sclerosis: Developing a research agenda.

PubMed

Yeh, E Ann; Kinnett-Hopkins, Dominique; Grover, Stephanie A; Motl, Robert W

2015-11-01

Three-quarters of children with multiple sclerosis (MS) experience fatigue or depression, and progressive neurocognitive decline may be seen as early as two years after MS diagnosis. Furthermore, a higher magnetic resonance imaging disease burden is seen in pediatric-onset MS compared with adult-onset MS. To date, limited knowledge exists regarding behavioral methods for managing symptoms and disease progression in pediatric MS. To that end, this paper builds an evidence-based argument for the possible symptomatic and disease-modifying effects of exercise and physical activity in pediatric MS. This will be accomplished through: (a) a review of pediatric MS and its consequences; (b) a brief overview of physical activity and its consequences in children and adults with MS; and (c) a selective review of research on the neurological benefits of physical activity in pediatric populations. This topical review concludes with a list of 10 questions to guide future research on physical activity and pediatric MS. The objective of this paper is the provision of a research interest, focus and agenda involving pediatric MS and its lifelong management though exercise and physical activity behavior. Such an agenda is critical as the effects and maintenance of physical activity and exercise track across the lifespan, particularly when developed in the early stages of life. © The Author(s), 2015.

Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution

PubMed Central

Fredman, Gabrielle; Serhan, Charles N.

2011-01-01

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators. PMID:21711247

Impaired Local Production of Proresolving Lipid Mediators in Obesity and 17-HDHA as a Potential Treatment for Obesity-Associated Inflammation

PubMed Central

Neuhofer, Angelika; Zeyda, Maximilian; Mascher, Daniel; Itariu, Bianca K.; Murano, Incoronata; Leitner, Lukas; Hochbrugger, Eva E.; Fraisl, Peter; Cinti, Saverio; Serhan, Charles N.; Stulnig, Thomas M.

2013-01-01

Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3–derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3–derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications. PMID:23349501

Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation.

PubMed

Neuhofer, Angelika; Zeyda, Maximilian; Mascher, Daniel; Itariu, Bianca K; Murano, Incoronata; Leitner, Lukas; Hochbrugger, Eva E; Fraisl, Peter; Cinti, Saverio; Serhan, Charles N; Stulnig, Thomas M

2013-06-01

Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3-derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3-derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakayama, T.; Kubo, O.; Shingaya, Y.

the research of advanced materials based on nanoscience and nanotechnology, it is often desirable to measure nanoscale local electrical conductivity at a designated position of a given sample. For this purpose, multiple-probe scanning probe microscopes (MP-SPMs), in which two, three or four scanning tunneling microscope (STM) or atomic force microscope (AFM) probes are operated independently, have been developed. Each probe in an MP-SPM is used not only for observing high-resolution STM or AFM images but also for forming an electrical contact enabling nanoscale local electrical conductivity measurement. The world's first double-probe STM (DP-STM) developed by the authors, which was subsequentlymore » modified to a triple-probe STM (TP-STM), has been used to measure the conductivities of one-dimensional metal nanowires and carbon nanotubes and also two-dimensional molecular films. A quadruple-probe STM (QP-STM) has also been developed and used to measure the conductivity of two-dimensional molecular films without the ambiguity of contact resistance between the probe and sample. Moreover, a quadruple-probe AFM (QP-AFM) with four conductive tuning-fork-type self-detection force sensing probes has been developed to measure the conductivity of a nanostructure on an insulating substrate. A general-purpose computer software to control four probes at the same time has also been developed and used in the operation of the QP-AFM. These developments and applications of MP-SPMs are reviewed in this paper.« less

Step-height standards based on the rapid formation of monolayer steps on the surface of layered crystals

NASA Astrophysics Data System (ADS)

Komonov, A. I.; Prinz, V. Ya.; Seleznev, V. A.; Kokh, K. A.; Shlegel, V. N.

2017-07-01

Metrology is essential for nanotechnology, especially for structures and devices with feature sizes going down to nm. Scanning probe microscopes (SPMs) permits measurement of nanometer- and subnanometer-scale objects. Accuracy of size measurements performed using SPMs is largely defined by the accuracy of used calibration measures. In the present publication, we demonstrate that height standards of monolayer step (∼1 and ∼0.6 nm) can be easily prepared by cleaving Bi2Se3 and ZnWO4 layered single crystals. It was shown that the conducting surface of Bi2Se3 crystals offers height standard appropriate for calibrating STMs and for testing conductive SPM probes. Our AFM study of the morphology of freshly cleaved (0001) Bi2Se3 surfaces proved that such surfaces remained atomically smooth during a period of at least half a year. The (010) surfaces of ZnWO4 crystals remained atomically smooth during one day, but already two days later an additional nanorelief of amplitude ∼0.3 nm appeared on those surfaces. This relief, however, did not further grow in height, and it did not hamper the calibration. Simplicity and the possibility of rapid fabrication of the step-height standards, as well as their high stability, make these standards available for a great, permanently growing number of users involved in 3D printing activities.

Subregional laminar cartilage MR spin-spin relaxation times (T2) in osteoarthritic knees with and without medial femorotibial cartilage loss - data from the Osteoarthritis Initiative (OAI).

PubMed

Wirth, W; Maschek, S; Beringer, P; Eckstein, F

2017-08-01

To explore whether subregional laminar femorotibial cartilage spin-spin relaxation time (T2) is associated with subsequent radiographic progression and cartilage loss and/or whether one-year change in subregional laminar femorotibial cartilage T2 is associated with concurrent progression in knees with established radiographic OA (ROA). In this case-control study, Osteoarthritis Initiative (OAI) knees with medial femorotibial progression were selected based on one-year loss in both quantitative cartilage thickness Magnetic resonance imaging (MRI) and radiographic joint space width (JSW). Non-progressor knees were matched by sex, Body mass index (BMI), baseline Kellgren-Lawrence-grade (2/3), and pain. Baseline and one-year follow-up superficial and deep cartilage T2 was analyzed in 16 femorotibial subregions using multi-echo spin-echo MRI. 37 knees showed medial femorotibial progression whereas 37 matched controls had no medial or lateral compartment progression. No statistically significant baseline differences between progressor and non-progressor knees in medial femorotibial cartilage T2 were observed in the superficial (48.9 ± 3.0 ms; 95% CI: [47.9, 49.9] vs 47.8 ± 3.6 ms; 95% CI: [46.6, 49.0], P = 0.07) or deep cartilage layer (40.8 ± 3.6 ms; 95% CI: [39.5, 42.0] vs 40.1 ± 4.7 ms; 95% CI: [38.5, 41.6], P = 0.29). Concurrent T2 change was more pronounced in the deep than the superficial cartilage layer. In the medial femorotibial compartment (MFTC), longitudinal change was greater in the deep layer of progressor than non-progressor knees (1.8 ± 4.5 ms; 95% CI: [0.3, 3.3] vs -0.2 ± 1.9 ms; 95% CI: [-0.8, 0.5], P = 0.02), whereas no difference was observed in the superficial layer. Medial compartment cartilage T2 did not appear to be a strong prognostic factor for subsequent structural progression in the same compartment of knees with established ROA, when appropriately controlling for covariates. Yet, deep layer T2 change in the medial compartment occurred concurrent with medial femorotibial progression. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Brain reserve against physical disability progression over 5 years in multiple sclerosis.

PubMed

Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M; Meani, Alessandro; Mesaros, Sarlota; Drulovic, Jelena; Preziosa, Paolo; Habeck, Christian G; Filippi, Massimo

2016-05-24

The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02-0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed. © 2016 American Academy of Neurology.

Access, delivery and perceived efficacy of physiotherapy and use of complementary and alternative therapies by people with progressive multiple sclerosis in the United Kingdom: An online survey.

PubMed

Campbell, Evan; Coulter, Elaine; Mattison, Paul; McFadyen, Angus; Miller, Linda; Paul, Lorna

2017-02-01

All people with progressive MS in the United Kingdom should have access to physiotherapy through the National Health Service (NHS). However levels of access and delivery are unknown. Furthermore there is no research on perceived efficacy of physiotherapy or the use of complementary and alternative medicine in people with progressive MS in the United Kingdom. An online survey was carried out via the UK MS Register. Inclusion criteria were diagnosis of progressive MS, a member of UK MS Register and 18 years or older. The survey asked participants regarding access and delivery of physiotherapy; perceived efficacy of physiotherapy and interventions received; barriers to accessing physiotherapy and use of complementary and alternative medicine. The following additional data were supplied from the UK MS Register: demographics, EQ5D, MSIS-29 physical and psychological sub-scales and geographical data. Total number of respondents was 1,298 from an identified 2,538 potential registrants: 87% could access physiotherapy services, 77% received physiotherapy from the NHS and 32% were currently receiving physiotherapy. The most common interventions received were home exercise programme (86%), exercises with a physiotherapist (74%) and advice/education (67%). 40% had recently used complementary and alternative medicine. Perceived efficacy of physiotherapy was high with 70% reporting it to be either 'beneficial' or 'very beneficial'. Main barriers to accessing physiotherapy were mobility, fatigue, continence, transport issues, requiring someone to go with them and pain. Access to physiotherapy was high with most people reporting it as beneficial. However 13% reported not having access indicating a gap in accessibility. Considering some of the barriers reported may allow physiotherapy services to address this gap in accessibility. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model

NASA Astrophysics Data System (ADS)

Chen, Deying; Su, Xiaoling; Wang, Nan; Li, Yunong; Yin, Hua; Li, Liang; Li, Lanjuan

2017-01-01

We report a chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) method generally applicable for tracking metabolomic changes from samples collected in an animal model for studying disease development and treatment. A rat model of surgically induced osteoarthritis (OA) was used as an example to illustrate the workflow and technical performance. Experimental duplicate analyses of 234 plasma samples were carried out using dansylation labeling LC-MS targeting the amine/phenol submetabolome. These samples composed of 39 groups (6 rats per group) were collected at multiple time points with sham operation, OA control group, and OA rats with treatment, separately, using glucosamine/Celecoxib and three traditional Chinese medicines (Epimedii folium, Chuanxiong Rhizoma and Bushen-Huoxue). In total, 3893 metabolites could be detected and 2923 of them were consistently detected in more than 50% of the runs. This high-coverage submetabolome dataset could be used to track OA progression and treatment. Many differentiating metabolites were found and 11 metabolites including 2-aminoadipic acid, saccharopine and GABA were selected as potential biomarkers of OA progression and OA treatment. This study illustrates that CIL LC-MS is a very useful technique for monitoring incremental metabolomic changes with high coverage and accuracy for studying disease progression and treatment in animal models.

Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model

PubMed Central

Chen, Deying; Su, Xiaoling; Wang, Nan; Li, Yunong; Yin, Hua; Li, Liang; Li, Lanjuan

2017-01-01

We report a chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) method generally applicable for tracking metabolomic changes from samples collected in an animal model for studying disease development and treatment. A rat model of surgically induced osteoarthritis (OA) was used as an example to illustrate the workflow and technical performance. Experimental duplicate analyses of 234 plasma samples were carried out using dansylation labeling LC-MS targeting the amine/phenol submetabolome. These samples composed of 39 groups (6 rats per group) were collected at multiple time points with sham operation, OA control group, and OA rats with treatment, separately, using glucosamine/Celecoxib and three traditional Chinese medicines (Epimedii folium, Chuanxiong Rhizoma and Bushen-Huoxue). In total, 3893 metabolites could be detected and 2923 of them were consistently detected in more than 50% of the runs. This high-coverage submetabolome dataset could be used to track OA progression and treatment. Many differentiating metabolites were found and 11 metabolites including 2-aminoadipic acid, saccharopine and GABA were selected as potential biomarkers of OA progression and OA treatment. This study illustrates that CIL LC-MS is a very useful technique for monitoring incremental metabolomic changes with high coverage and accuracy for studying disease progression and treatment in animal models. PMID:28091618

Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes.

PubMed

Ruano, Luis; Portaccio, Emilio; Goretti, Benedetta; Niccolai, Claudia; Severo, Milton; Patti, Francesco; Cilia, Sabina; Gallo, Paolo; Grossi, Paola; Ghezzi, Angelo; Roscio, Marco; Mattioli, Flavia; Stampatori, Chiara; Trojano, Maria; Viterbo, Rosa Gemma; Amato, Maria Pia

2017-08-01

There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

MRI Correlates of Disability in African-Americans with Multiple Sclerosis

PubMed Central

Howard, Jonathan; Battaglini, Marco; Babb, James Scott; Arienzo, Donatello; Holst, Brigitte; Omari, Mirza; De Stefano, Nicola; Herbert, Joseph; Inglese, Matilde

2012-01-01

Objectives Multiple sclerosis (MS) in African-Americans (AAs) is characterized by more rapid disease progression and poorer response to treatment than in Caucasian-Americans (CAs). MRI provides useful and non-invasive tools to investigate the pathological substrate of clinical progression. The aim of our study was to compare MRI measures of brain damage between AAs and CAs with MS. Methods Retrospective analysis of 97 AAs and 97 CAs with MS matched for age, gender, disease duration and age at MRI examination. Results AA patients had significantly greater T2- (p = 0.001) and T1-weighted (p = 0.0003) lesion volumes compared to CA patients. In contrast, measurements of global and regional brain volume did not significantly differ between the two ethnic groups (p>0.1). Conclusions By studying a quite large sample of well demographically and clinically matched CA and AA patients with a homogeneous MRI protocol we showed that higher lesion accumulation, rather than pronounced brain volume decrease might explain the early progress to ambulatory assistance of AAs with MS. PMID:22900088

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

PubMed

Tourbah, Ayman; Lebrun-Frenay, Christine; Edan, Gilles; Clanet, Michel; Papeix, Caroline; Vukusic, Sandra; De Sèze, Jerome; Debouverie, Marc; Gout, Olivier; Clavelou, Pierre; Defer, Gilles; Laplaud, David-Axel; Moreau, Thibault; Labauge, Pierre; Brochet, Bruno; Sedel, Frédéric; Pelletier, Jean

2016-11-01

Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated. © The Author(s), 2016.

Usefulness of optic nerve ultrasound to predict clinical progression in multiple sclerosis.

PubMed

Pérez Sánchez, S; Eichau Madueño, S; Rus Hidalgo, M; Domínguez Mayoral, A M; Vilches-Arenas, A; Navarro Mascarell, G; Izquierdo, G

2018-03-21

Progressive neuronal and axonal loss are considered the main causes of disability in patients with multiple sclerosis (MS). The disease frequently involves the visual system; the accessibility of the system for several functional and structural tests has made it a model for the in vivo study of MS pathogenesis. Orbital ultrasound is a non-invasive technique that enables various structures of the orbit, including the optic nerve, to be evaluated in real time. We conducted an observational, ambispective study of MS patients. Disease progression data were collected. Orbital ultrasound was performed on all patients, with power set according to the 'as low as reasonably achievable' (ALARA) principle. Optical coherence tomography (OCT) data were also collected for those patients who underwent the procedure. Statistical analysis was conducted using SPSS version 22.0. Disease progression was significantly correlated with ultrasound findings (P=.041 for the right eye and P=.037 for the left eye) and with Expanded Disability Status Scale (EDSS) score at the end of the follow-up period (P=.07 for the right eye and P=.043 for the left eye). No statistically significant differences were found with relation to relapses or other clinical variables. Ultrasound measurement of optic nerve diameter constitutes a useful, predictive factor for the evaluation of patients with MS. Smaller diameters are associated with poor clinical progression and greater disability (measured by EDSS). Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Intersections of pathways involving biotin and iron relative to therapeutic mechanisms for progressive multiple sclerosis.

PubMed

Heidker, Rebecca M; Emerson, Mitchell R; LeVine, Steven M

2016-12-01

While there are a variety of therapies for relapsing remitting multiple sclerosis (MS), there is a lack of treatments for progressive MS. An early study indicated that high dose biotin therapy has beneficial effects in approximately 12-15% of patients with progressive MS. The mechanisms behind the putative improvements seen with biotin therapy are not well understood, but have been postulated to include: 1) improving mitochondrial function which is impaired in MS, 2) increasing synthesis of lipids and cholesterol to facilitate remyelination, and 3) affecting gene expression. We suggest one reason that a greater percentage of patients with MS didn't respond to biotin therapy is the inaccessibility or lack of other nutrients, such as iron. In addition to biotin, iron (or heme) is necessary for energy production, biosynthesis of cholesterol and lipids, and for some protective mechanisms. Both biotin and iron are required for myelination during development, and by inference, remyelination. However, iron can also play a role in the pathology of MS. Increased deposition of iron can occur in some CNS structures possibly promoting oxidative damage while low iron levels can occur in other areas. Thus, the potential, detrimental effects of iron need to be considered together with the need for iron to support metabolic demands associated with repair and/or protective processes. We propose the optimal utilization of iron may be necessary to maximize the beneficial effects of biotin. This review will examine the interactions between biotin and iron in pathways that may have therapeutic or pathogenic implications for MS.

A web-based decision support tool for prognosis simulation in multiple sclerosis.

PubMed

Veloso, Mário

2014-09-01

A multiplicity of natural history studies of multiple sclerosis provides valuable knowledge of the disease progression but individualized prognosis remains elusive. A few decision support tools that assist the clinician in such task have emerged but have not received proper attention from clinicians and patients. The objective of the current work is to implement a web-based tool, conveying decision relevant prognostic scientific evidence, which will help clinicians discuss prognosis with individual patients. Data were extracted from a set of reference studies, especially those dealing with the natural history of multiple sclerosis. The web-based decision support tool for individualized prognosis simulation was implemented with NetLogo, a program environment suited for the development of complex adaptive systems. Its prototype has been launched online; it enables clinicians to predict both the likelihood of CIS to CDMS conversion, and the long-term prognosis of disability level and SPMS conversion, as well as assess and monitor the effects of treatment. More robust decision support tools, which convey scientific evidence and satisfy the needs of clinical practice by helping clinicians discuss prognosis expectations with individual patients, are required. The web-based simulation model herein introduced proposes to be a step forward toward this purpose. Copyright © 2014 Elsevier B.V. All rights reserved.

Can a low-cost webcam be used for a remote neurological exam?

PubMed

Wood, Jeffrey; Wallin, Mitchell; Finkelstein, Joseph

2013-01-01

Multiple sclerosis (MS) is a demyelinating and axonal degenerative disease of the central nervous system. It is the most common progressive neurological disorder of young adults affecting over 1 million persons worldwide. Despite the increased use of neuroimaging and other tools to measure MS morbidity, the neurological examination remains the primary method to document relapses and progression in disease. The goal of this study was to demonstrate the feasibility and validity of using a low-cost webcam for remote neurological examination in home-setting for patients with MS. Using cross-over design, 20 MS patients were evaluated in-person and via remote televisit and results of the neurological evaluation were compared. Overall, we found that agreement between face-to-face and remote EDSS evaluation was sufficient to provide clinically valid information. Another important finding of this study was high acceptance of patients and their providers of using remote televisits for conducting neurological examinations at MS patient homes. The results of this study demonstrated potential of using low-cost webcams for remote neurological exam in patients with MS.

Functional protease profiling for diagnosis of malignant disease.

PubMed

Findeisen, Peter; Neumaier, Michael

2012-01-01

Clinical proteomic profiling by mass spectrometry (MS) aims at uncovering specific alterations within mass profiles of clinical specimens that are of diagnostic value for the detection and classification of various diseases including cancer. However, despite substantial progress in the field, the clinical proteomic profiling approaches have not matured into routine diagnostic applications so far. Their limitations are mainly related to high-abundance proteins and their complex processing by a multitude of endogenous proteases thus making rigorous standardization difficult. MS is biased towards the detection of low-molecular-weight peptides. Specifically, in serum specimens, the particular fragments of proteolytically degraded proteins are amenable to MS analysis. Proteases are known to be involved in tumour progression and tumour-specific proteases are released into the blood stream presumably as a result of invasive progression and metastasis. Thus, the determination of protease activity in clinical specimens from patients with malignant disease can offer diagnostic and also therapeutic options. The identification of specific substrates for tumour proteases in complex biological samples is challenging, but proteomic screens for proteases/substrate interactions are currently experiencing impressive progress. Such proteomic screens include peptide-based libraries, differential isotope labelling in combination with MS, quantitative degradomic analysis of proteolytically generated neo-N-termini, monitoring the degradation of exogenous reporter peptides with MS, and activity-based protein profiling. In the present article, we summarize and discuss the current status of proteomic techniques to identify tumour-specific protease-substrate interactions for functional protease profiling. Thereby, we focus on the potential diagnostic use of the respective approaches. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cognitive Impairment in MS Linked to Structural and Functional Connectivity

DTIC Science & Technology

2016-10-01

AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is the most...9 9. Appendices……………………………………………………………9 Krupp MS130103  2  Abstract Multiple sclerosis (MS) is the most common progressive neurologic...This symptom represents a major concern for many individuals living with multiple sclerosis (MS). Unfortunately, no reliable treatments exist to

[Progress in the application of laser ablation ICP-MS to surface microanalysis in material science].

PubMed

Zhang, Yong; Jia, Yun-hai; Chen, Ji-wen; Shen, Xue-jing; Liu, Ying; Zhao, Leiz; Li, Dong-ling; Hang, Peng-cheng; Zhao, Zhen; Fan, Wan-lun; Wang, Hai-zhou

2014-08-01

In the present paper, apparatus and theory of surface analysis is introduced, and the progress in the application of laser ablation ICP-MS to microanalysis in ferrous, nonferrous and semiconductor field is reviewed in detail. Compared with traditional surface analytical tools, such as SEM/EDS (scanning electron microscopy/energy dispersive spectrum), EPMA (electron probe microanalysis analysis), AES (auger energy spectrum), etc. the advantage is little or no sample preparation, adjustable spatial resolution according to analytical demand, multi-element analysis and high sensitivity. It is now a powerful complementary method to traditional surface analytical tool. With the development of LA-ICP-MS technology maturing, more and more analytical workers will use this powerful tool in the future, and LA-ICP-MS will be a super star in elemental analysis field just like LIBS (Laser-induced breakdown spectroscopy).

Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

PubMed

Dahdaleh, Maurice; Alroughani, Raed; Aljumah, Mohammed; AlTahan, Abdulrahman; Alsharoqi, Issa; Bohlega, Saeed A; Daif, Abdulkader; Deleu, Dirk; Inshasi, Jihad; Karabudak, Rana; Sahraian, Mohammed A; Taha, Karim; Yammout, Bassem I; Zakaria, Magd

2017-10-01

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.

Progression, Symptoms and Psychosocial Concerns among Those Severely Affected by Multiple Sclerosis: A Mixed-Methods Cross-Sectional Study of Black Caribbean and White British People

PubMed Central

Koffman, Jonathan; Gao, Wei; Goddard, Cassie; Burman, Rachel; Jackson, Diana; Shaw, Pauline; Barnes, Fiona; Silber, Eli; Higginson, Irene J.

2013-01-01

Objective Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS. Design Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach. Results Median EDSS for both groups was (6.5; range: 6.0–9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients’ reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms. Conclusions Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity. PMID:24098384

Progression, symptoms and psychosocial concerns among those severely affected by multiple sclerosis: a mixed-methods cross-sectional study of Black Caribbean and White British people.

PubMed

Koffman, Jonathan; Gao, Wei; Goddard, Cassie; Burman, Rachel; Jackson, Diana; Shaw, Pauline; Barnes, Fiona; Silber, Eli; Higginson, Irene J

2013-01-01

Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS. Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach. Median EDSS for both groups was (6.5; range: 6.0-9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients' reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms. Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity.

Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice.

PubMed

Peferoen, Laura A N; Breur, Marjolein; van de Berg, Sarah; Peferoen-Baert, Regina; Boddeke, Erik H W G M; van der Valk, Paul; Pryce, Gareth; van Noort, Johannes M; Baker, David; Amor, Sandra

2016-10-01

Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease. © 2016 John Wiley & Sons Ltd.

The development of a disease oriented eFolder for multiple sclerosis decision support

NASA Astrophysics Data System (ADS)

Ma, Kevin; Jacobs, Colin; Fernandez, James; Amezcua, Lilyana; Liu, Brent

2010-03-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The chronic nature of MS necessitates multiple MRI studies to track disease progression. Currently, MRI assessment of multiple sclerosis requires manual lesion measurement and yields an estimate of lesion volume and change that is highly variable and user-dependent. In the setting of a longitudinal study, disease trends and changes become difficult to extrapolate from the lesions. In addition, it is difficult to establish a correlation between these imaged lesions and clinical factors such as treatment course. To address these clinical needs, an MS specific e-Folder for decision support in the evaluation and assessment of MS has been developed. An e-Folder is a disease-centric electronic medical record in contrast to a patient-centric electronic health record. Along with an MS lesion computer aided detection (CAD) package for lesion load, location, and volume, clinical parameters such as patient demographics, disease history, clinical course, and treatment history are incorporated to make the e-Folder comprehensive. With the integration of MRI studies together with related clinical data and informatics tools designed for monitoring multiple sclerosis, it provides a platform to improve the detection of treatment response in patients with MS. The design and deployment of MS e-Folder aims to standardize MS lesion data and disease progression to aid in decision making and MS-related research.

Spermine modulates the expression of two probable polyamine transporter genes and determines growth responses to cadaverine in Arabidopsis.

PubMed

Sagor, G H M; Berberich, Thomas; Kojima, Seiji; Niitsu, Masaru; Kusano, Tomonobu

2016-06-01

Two genes, LAT1 and OCT1 , are likely to be involved in polyamine transport in Arabidopsis. Endogenous spermine levels modulate their expression and determine the sensitivity to cadaverine. Arabidopsis spermine (Spm) synthase (SPMS) gene-deficient mutant was previously shown to be rather resistant to the diamine cadaverine (Cad). Furthermore, a mutant deficient in polyamine oxidase 4 gene, accumulating about twofold more of Spm than wild type plants, showed increased sensitivity to Cad. It suggests that endogenous Spm content determines growth responses to Cad in Arabidopsis thaliana. Here, we showed that Arabidopsis seedlings pretreated with Spm absorbs more Cad and has shorter root growth, and that the transgenic Arabidopsis plants overexpressing the SPMS gene are hypersensitive to Cad, further supporting the above idea. The transgenic Arabidopsis overexpressing L-Amino acid Transporter 1 (LAT1) absorbed more Cad and showed increased Cad sensitivity, suggesting that LAT1 functions as a Cad importer. Recently, other research group reported that Organic Cation Transporter 1 (OCT1) is a causal gene which determines the Cad sensitivity of various Arabidopsis accessions. Furthermore, their results suggested that OCT1 is involved in Cad efflux. Thus we monitored the expression of OCT1 and LAT1 during the above experiments. Based on the results, we proposed a model in which the level of Spm content modulates the expression of OCT1 and LAT1, and determines Cad sensitivity of Arabidopsis.

Genome-wide identification, phylogenetic analysis, and expression profiling of polyamine synthesis gene family members in tomato.

PubMed

Liu, Taibo; Huang, Binbin; Chen, Lin; Xian, Zhiqiang; Song, Shiwei; Chen, Riyuan; Hao, Yanwei

2018-06-30

Polyamines (PAs), including putrescine (Put), spermidine (Spd), spermine (Spm), and thermospermine (T-Spm), play key roles in plant development, including fruit setting and ripening, morphogenesis, and abiotic/biotic stress. Their functions appear to be intimately related to their synthesis, which occurs via arginine/ornithine decarboxylase (ADC/ODC), Spd synthase (SPDS), Spm synthase (SPMS), and Acaulis5 (ACL5), respectively. Unfortunately, the expression and function of these PA synthesis-relate genes during specific developmental process or under stress have not been fully elucidated. Here, we present the results of a genome-wide analysis of the PA synthesis genes (ADC, ODC, SPDS, SPMS, ACL5) in the tomato (Solanum lycopersicum). In total, 14 PA synthesis-related genes were identified. Further analysis of their structures, conserved domains, phylogenetic trees, predicted subcellular localization, and promoter cis-regulatory elements were analyzed. Furthermore, we also performed experiments to evaluate their tissue expression patterns and under hormone and various stress treatments. To our knowledge, this is the first study to elucidate the mechanisms underlying PA function in this variety of tomato. Taken together, these data provide valuable information for future functional characterization of specific genes in the PA synthesis pathway in this and other plant species. Although additional research is required, the insight gained by this and similar studies can be used to improve our understanding of PA metabolism ultimately leading to more effective and consistent plant cultivation. Copyright © 2018 Elsevier B.V. All rights reserved.

DEVELOPMENT OF AN ELECTROSPRAY LC/MS LIBRARY IDENTIFICATION PROTOCOL FOR THE SCREENING OF ORGANIC CONTAMINANTS IN DRINKING WATER

EPA Science Inventory

A significant number (80%) of organic contaminants that represent health risks in drinking water are better suited to screening by LC/MS rather than GC/MS analysis. We report progress with the draft Library System Protocol 1.1 from a round robin of private, state and federal lab...

Quantitative measures detect sensory and motor impairments in multiple sclerosis

PubMed Central

Newsome, Scott D.; Wang, Joseph I.; Kang, Jonathan Y.; Calabresi, Peter A.; Zackowski, Kathleen M.

2011-01-01

Background Sensory and motor dysfunction in multiple sclerosis (MS) is often assessed with rating scales which rely heavily on clinical judgment. Quantitative devices may be more precise than rating scales. Objective To quantify lower extremity sensorimotor measures in individuals with MS, evaluate the extent to which they can detect functional systems impairments, and determine their relationship to global disability measures. Methods We tested 145 MS subjects and 58 controls. Vibration thresholds were quantified using a Vibratron-II device. Strength was quantified by a hand-held dynamometer. We also recorded Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW). T-tests and Wilcoxon-rank sum were used to compare group data. Spearman correlations were used to assess relationships between each measure. We also used a step-wise linear regression model to determine how much the quantitative measures explain the variance in the respective functional systems scores (FSS). Results EDSS scores ranged from 0-7.5, mean disease duration was 10.4±9.6 years, and 66% were female. In RRMS, but not progressive MS, poorer vibration sensation correlated with a worse EDSS score, whereas progressive groups’ ankle/hip strength changed significantly with EDSS progression. Interestingly, not only did sensorimotor measures significantly correlate with global disability measures (EDSS), but they had improved sensitivity, as they detected impairments in up to 32% of MS subjects with normal sensory FSS. Conclusions Sensory and motor deficits can be quantified using clinically accessible tools and distinguish differences among MS subtypes. We show that quantitative sensorimotor measures are more sensitive than FSS from the EDSS. These tools have the potential to be used as clinical outcome measures in practice and for future MS clinical trials of neurorehabilitative and neuroreparative interventions. PMID:21458828

Information processing efficiency in patients with multiple sclerosis.

PubMed

Archibald, C J; Fisk, J D

2000-10-01

Reduced information processing efficiency, consequent to impaired neural transmission, has been proposed as underlying various cognitive problems in patients with Multiple Sclerosis (MS). This study employed two measures developed from experimental psychology that control for the potential confound of perceptual-motor abnormalities (Salthouse, Babcock, & Shaw, 1991; Sternberg, 1966, 1969) to assess the speed of information processing and working memory capacity in patients with mild to moderate MS. Although patients had significantly more cognitive complaints than neurologically intact matched controls, their performance on standard tests of immediate memory span did not differ from control participants and their word list learning was within normal limits. On the experimental measures, both relapsing-remitting and secondary-progressive patients exhibited significantly slowed information processing speed relative to controls. However, only the secondary-progressive patients had an additional decrement in working memory capacity. Depression, fatigue, or neurologic disability did not account for performance differences on these measures. While speed of information processing may be slowed early in the disease process, deficits in working memory capacity may appear only as there is progression of MS. It is these latter deficits, however, that may underlie the impairment of new learning that patients with MS demonstrate.

Distress improves after mindfulness training for progressive MS: A pilot randomised trial.

PubMed

Bogosian, A; Chadwick, P; Windgassen, S; Norton, S; McCrone, P; Mosweu, I; Silber, E; Moss-Morris, R

2015-08-01

Mindfulness-based interventions have been shown to effectively reduce anxiety, depression and pain in patients with chronic physical illnesses. We assessed the potential effectiveness and cost-effectiveness of a specially adapted Skype distant-delivered mindfulness intervention, designed to reduce distress for people affected by primary and secondary progressive MS. Forty participants were randomly assigned to the eight-week intervention (n = 19) or a waiting-list control group (n = 21). Participants completed standardised questionnaires to measure mood, impact of MS and symptom severity, quality of life and service costs at baseline, post-intervention and three-month follow-up. Distress scores were lower in the intervention group compared with the control group at post-intervention and follow-up (p < 0.05), effect size -0.67 post-intervention and -0.97 at follow-up. Mean scores for pain, fatigue, anxiety, depression and impact of MS were reduced for the mindfulness group compared with control group at post-therapy and follow-up; effect sizes ranged from -0.27 to -0.99 post-intervention and -0.29 to -1.12 at follow-up. There were no differences in quality-adjusted life years, but an 87.4% probability that the intervention saves on service costs and improves outcome. A mindfulness intervention delivered through Skype video conferences appears accessible, feasible and potentially effective and cost-effective for people with progressive MS. © The Author(s), 2015.

Evaluating Soluble EMMPRIN as a Marker of Disease Activity in Multiple Sclerosis: Studies of Serum and Cerebrospinal Fluid.

PubMed

Kaushik, Deepak K; Yong, Heather Y F; Hahn, Jennifer N; Silva, Claudia; Casha, Steven; Hurlbert, R John; Jacques, Francois H; Lisak, Robert; Khan, Omar; Ionete, Carolina; Larochelle, Catherine; Prat, Alex; Bar-Or, Amit; Yong, V Wee

2016-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is an inducer of matrix metalloproteinases and has roles in leukocyte activation and migration. We reported previously that in MS and its animal model, experimental autoimmune encephalomyelitis, cell surface-associated EMMPRIN was significantly elevated in leukocytes around inflammatory perivascular cuffs in the CNS. In this study we report that activated T-cells can secrete soluble form of EMMPRIN (sEMMPRIN) upon activation. As sEMMPRIN is also present in biological fluids, we determined whether sEMMPRIN is altered in the CSF and sera of MS subjects. Sera from individuals without neurological conditions served as controls, while CSFs collected from subjects undergoing discectomy, and without evidence of CNS pathology, were used as a comparator group. We found that serum levels of sEMMPRIN from clinically stable MS patients or other inflammatory conditions did not differ from control subjects. Paired serum and CSF samples demonstrated poor correlation of sEMMPRIN. Interestingly, sEMMPRIN levels were approximately 60% higher in CSFs compared to sera. sEMMPRIN CSF levels were significantly higher in secondary progressive compared to primary progressive subjects. Thus we conclude that measurement of sEMMPRIN in serum is not informative for disease activity in MS. The differential expression of sEMMPRIN in the CSF of primary and secondary progressive MS invites hypotheses of the still undefined roles of EMMPRIN in the CNS.

The effects of identification with a support group on the mental health of people with multiple sclerosis.

PubMed

Wakefield, Juliet R H; Bickley, Sarah; Sani, Fabio

2013-05-01

Multiple sclerosis (MS) is associated with various psychological problems, including depression and anxiety. Whilst MS support groups are intended to improve mental health, this goal is not always achieved. Taking a social identity approach, we hypothesise that it is the level of subjective identification with a support group (rather than simply support group membership per se) that positively affects the mental health of people with MS. 152 individuals with MS were recruited via UK MS support groups and completed a questionnaire. This included measures of support group identification, depression, anxiety and satisfaction with life, as well as control variables (education level and age). Analyses revealed that, as hypothesised, support group identification was significantly linked to depression, anxiety and satisfaction with life. Moreover, group identification explained a significant amount of variance in addition to that explained by education and age on each health outcome. Repeating the analysis to compare each of the three main sub-types of MS revealed these effects to be present for individuals with relapsing-remitting (RR) and Primary Progressive (PP) MS, but not for those with secondary progressive (SP) MS. We suggest that identifying highly with an MS support group has important positive outcomes for MS patients' mental health. This has implications for practicing clinicians: people with MS (particularly RRMS and PPMS) should be encouraged to engage with support groups, but more must be done to ensure they subjectively identify with these groups, rather than merely attend them. Copyright © 2013 Elsevier Inc. All rights reserved.

Immune-Inflammatory and Oxidative and Nitrosative Stress Biomarkers of Depression Symptoms in Subjects with Multiple Sclerosis: Increased Peripheral Inflammation but Less Acute Neuroinflammation.

PubMed

Kallaur, Ana Paula; Lopes, Josiane; Oliveira, Sayonara Rangel; Simão, Andrea Name Colado; Reiche, Edna Maria Vissoci; de Almeida, Elaine Regina Delicato; Morimoto, Helena Kaminami; de Pereira, Wildea Lice Carvalho Jennings; Alfieri, Daniele Frizon; Borelli, Sueli Donizete; Kaimen-Maciel, Domacio Ramon; Maes, Michael

2016-10-01

There is evidence that activated immune-inflammatory and oxidative and nitrosative stress (IO&NS) pathways play a role in the pathophysiology of multiple sclerosis (MS) and depression. This study examines serum levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10; peroxides (LOOH); nitric oxide metabolites (NOx); albumin; ferritin; C-reactive protein (CRP); and tumor necrosis factor (TNF)-β NcoI polymorphism (rs909253) and gadolinium-enhanced magnetic resonance imaging (MRI) scan in MS patients with (n = 42) and without (n = 108) depression and normal controls (n = 249). Depression is scored using the depressive subscale of the Hospital Anxiety and Depression Scale (HADS). The extent of neurological disability is measured using the Expanded Disability Status Scale (EDSS) at the same time of the abovementioned measurements and 5 years earlier. Disease progression is assessed as actual EDSS-EDSS 5 years earlier. Three variables discriminate MS patients with depression from those without depression, i.e., increased IL-6 and lower IL-4 and albumin. Binary logistic regression showed that MS with depression (versus no depression) was characterized by more gastrointestinal symptoms and disease progression, higher serum IL-6, and lower albumin levels. In subjects with MS, the HADS score was significantly predicted by three EDSS symptoms, i.e., pyramidal, gastrointestinal, and visual symptoms. Fifty-eight percent of the variance in the HADS score was predicted by gastrointestinal symptoms, visual symptoms, the TNFB1/B2 genotype, and contrast enhancement (both inversely associated). There were no significant associations between depression in MS and type of MS, duration of illness, age, sex, nicotine dependence, and body mass index. MS with depression is associated with signs of peripheral inflammation, more disability, disease progression, gastrointestinal and visual symptoms, but less contrast enhancement as compared to MS without depression. It is concluded that depression is part of the neurological symptoms of MS and that its expression is primed by peripheral inflammation while acute neuroinflammation and the TNFB1/B2 genotype may be protective.

Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

PubMed

Lundell, H; Svolgaard, O; Dogonowski, A-M; Romme Christensen, J; Selleberg, F; Soelberg Sørensen, P; Blinkenberg, M; Siebner, H R; Garde, E

2017-10-01

To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Multiple sclerosis with predominant, severe cognitive impairment

PubMed Central

Staff, Nathan P.; Lucchinetti, Claudia F.; Keegan, B. Mark

2009-01-01

Objective To describe the characteristics of multiple sclerosis (MS) presenting with severe cognitive impairment as its primary disabling manifestation. Design Retrospective case series. Setting Tertiary referral center. Patients Patients were identified through the Mayo Clinic data retrieval system (1996–2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course and radiological features. Main Outcome Measures Demographic, clinical, and radiological characteristics of the disease. Results Twelve patients were men. The median age of the first clinical symptom suggestive of CNS demyelination was 33 years, and severe MS-related cognitive impairment developed at a median of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n=9) or chronic progressive (n=14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%) and cortical symptoms and signs (e.g. seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain MRI demonstrated diffuse cerebral atrophy in 16 and gadolinium enhancing lesions in 11. Asymptomatic spinal cord MRI lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients. Conclusions We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be over represented in this phenotype. PMID:19752304

Information processing characteristics in subtypes of multiple sclerosis.

PubMed

De Sonneville, L M J; Boringa, J B; Reuling, I E W; Lazeron, R H C; Adèr, H J; Polman, C H

2002-01-01

The purpose of this study was to evaluate information processing characteristics in patients with multiple sclerosis (MS). We selected 53 patients with MS and 58 matched healthy controls. Using computerized tests, we investigated focused, divided, sustained attention, and executive function, and attempted to pinpoint deficits in attentional control to peripheral or central processing stages. The results substantiate the hypothesis that the slowing of attention-demanding (controlled) information processing underlying more complex cognitive skills is general, i.e. irrespective of type of controlled processing, with MS patients being 40% slower than controls. MS patients may suffer from focused, and divided and sustained attention deficits, as well as from compromised central processing stages, with secondary progressive (SP) patients showing the most extensive range of deficits, closely followed by primary progressive (PP) patients, while relapsing-remitting (RR) patients appear to be much less affected. General slowing appears to be highest in PP and SP type MS patients (50% slower) versus relapsing-remitting MS (24% slower). In contrast to most previous results, (complex) processing speed appeared to be robustly correlated with severity of MS as measured by the expanded disability status scale and with disease duration. Patients did much less differ in accuracy of processing from controls, suggesting the importance of using time strategies in planning everyday life and job activities to compensate for or alleviate MS-related speed handicaps. Copyright 2002 Elsevier Science Ltd.

Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis.

PubMed

Cree, B A C; Khan, O; Bourdette, D; Goodin, D S; Cohen, J A; Marrie, R A; Glidden, D; Weinstock-Guttman, B; Reich, D; Patterson, N; Haines, J L; Pericak-Vance, M; DeLoa, C; Oksenberg, J R; Hauser, S L

2004-12-14

African American (AA) individuals are thought to develop multiple sclerosis (MS) less frequently than Caucasian American (CA) individuals. To compare the clinical characteristics of AA and CA patients with MS. The clinical features of MS were compared in a large retrospective cohort of AA (n = 375) and CA (n = 427) subjects. The proportion of women to men was similar in AA and CA subjects (81% [AA] vs 77% [CA]; p = 0.122). There were no differences in the proportions of subjects with relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. The median time to diagnosis was 1 year after symptom onset in AA subjects and 2 years after symptom onset in CA subjects (p = 0.0013). The age at onset was approximately 2.5 years later in AA than CA subjects (33.7 vs 31.1 years; p = 0.0001). AA subjects presented with multisite signs and symptoms at disease onset more often than CA subjects (p = 0.018). Clinical involvement restricted to the optic nerves and spinal cord (opticospinal MS) occurred in 16.8% of AA patients compared with 7.9% of CA patients (p < 0.001). Transverse myelitis also occurred more frequently in AA subjects (28 vs 18%; p = 0.001). Survival analysis revealed that AA subjects were at higher risk for development of ambulatory disability than CA subjects. After adjusting for baseline variations and differences in therapeutic interventions, AAs were at 1.67-fold greater risk for requiring a cane to ambulate than CA patients (p < 0.001). There was a trend suggesting that AAs were also at greater risk for development of wheelchair dependency (p = 0.099). Adjusted Cox proportional hazard models showed that this effect was in part attributable to the older age at onset in AAs (p < 0.001). Compared with multiple sclerosis (MS) in Caucasian Americans, African American patients with MS have a greater likelihood of developing opticospinal MS and transverse myelitis and have a more aggressive disease course.

Demographics and clinical characteristics of episodic hypothermia in multiple sclerosis.

PubMed

Toledano, Michel; Weinshenker, Brian G; Kaufmann, Timothy J; Parisi, Joseph E; Paz Soldán, M Mateo

2018-03-01

Episodic hypothermia (EH) can occur in multiple sclerosis (MS). The putative mechanism is impairment of thermoregulation due to a presumed demyelinating hypothalamic lesion. To describe a cohort of patients with MS, who developed EH. Patients were identified through review of the Mayo Clinic electronic medical record (1996 to July 2015). Search terms were [multiple sclerosis] or [MS] within the diagnoses field and [hypothermia] within any field. We reviewed records for accuracy of diagnoses and abstracted relevant data. Magnetic resonance imaging (MRI) was reviewed for presence of hypothalamic lesions. Of 156 patients, 34 had concurrent MS and hypothermia. Thirty-two (94%) had progressive disease at EH onset. Median MS duration was 19.9 years, and median expanded disability status scale (EDSS) was 8.0. Most patients presented with alterations in consciousness. Infection was suspected as the precipitating factor in 19 (56%), but clinically/laboratory supported in only 9 (28%). MRI lesions were evident within the hypothalamus in only 4 (14%). EH occurs predominantly in patients with advanced secondary progressive MS. The major manifestation is altered consciousness. Infection is often suspected as causal, but infrequently confirmed. Although commonly implicated, hypothalamic lesions were rarely evident on MRI and were absent in two post-mortem evaluations.

Assessment of Central Visual Function in Patients with Retinitis Pigmentosa.

PubMed

Fujiwara, Kohta; Ikeda, Yasuhiro; Murakami, Yusuke; Tachibana, Takashi; Funatsu, Jun; Koyanagi, Yoshito; Nakatake, Shunji; Yoshida, Noriko; Nakao, Shintaro; Hisatomi, Toshio; Yoshida, Shigeo; Yoshitomi, Takeshi; Ishibashi, Tatsuro; Sonoda, Koh-Hei

2018-05-23

In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

PubMed

Touil, Hanane; Kobert, Antonia; Lebeurrier, Nathalie; Rieger, Aja; Saikali, Philippe; Lambert, Caroline; Fawaz, Lama; Moore, Craig S; Prat, Alexandre; Gommerman, Jennifer; Antel, Jack P; Itoyama, Yasuto; Nakashima, Ichiro; Bar-Or, Amit

2018-04-19

The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

Cytotoxic CD4+ T Cells Drive Multiple Sclerosis Progression.

PubMed

Peeters, Liesbet M; Vanheusden, Marjan; Somers, Veerle; Van Wijmeersch, Bart; Stinissen, Piet; Broux, Bieke; Hellings, Niels

2017-01-01

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP ( P  = 0.003, R 2  = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years ( P  = 0.005, R 2  = 0.29) and with EP and EDSS after 5 years ( P  = 0.008, R 2  = 0.42 and P  = 0.003, R 2  = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.

Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis.

PubMed

Curtin, François; Perron, Hervé; Faucard, Raphael; Porchet, Hervé; Lang, Alois B

2015-10-01

Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics-in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-β. GNbAC1 as a new MSRV-Env-antagonist mAb could be a specific and causal treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.

Recent progress in the analysis of uremic toxins by mass spectrometry.

PubMed

Niwa, Toshimitsu

2009-09-01

Mass spectrometry (MS) has been successfully applied for the identification and quantification of uremic toxins and uremia-associated modified proteins. This review focuses on recent progress in the analysis of uremic toxins by using MS. Uremic toxins include low-molecular-weight compounds (e.g., indoxyl sulfate, p-cresol sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, asymmetric dimethylarginine), middle-molecular-weight peptides, and proteins modified with advanced glycation and oxidation. These uremic toxins are considered to be involved in a variety of symptoms which may appear in patients with stage 5 chronic kidney disease. Based on MS analysis of these uremic toxins, the pathogenesis of the uremic symptoms will be elucidated to prevent and manage the symptoms.

Earnings and Financial Compensation from Social Security Systems Correlate Strongly with Disability for Multiple Sclerosis Patients.

PubMed

Kavaliunas, Andrius; Wiberg, Michael; Tinghög, Petter; Glaser, Anna; Gyllensten, Hanna; Alexanderson, Kristina; Hillert, Jan

2015-01-01

Multiple sclerosis (MS) patients earn lower incomes and receive higher benefits. However, there is limited knowledge of how this is correlated with their disability. To elucidate sources and levels of income among MS patients with different disability, assessed with the Expanded Disability Status Scale. A total of 7929 MS patients aged 21-64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic and truncated linear regression models were used to estimate differences between MS patients regarding earnings, disability pension, sickness absence, disability allowance, unemployment compensation, and social assistance. The average level of earnings was ten times lower and the average level of health- related benefits was four times higher when comparing MS patients with severe and mild disability. MS patients with severe disability had on average SEK 166,931 less annual income from earnings and SEK 54,534 more income from benefits compared to those with mild disability. The combined average income for MS patients was 35% lower when comparing patients in the same groups. The adjusted risk ratio for having earnings among MS patients with severe disability compared to the patients with mild disability was 0.33 (95% CI 0.29-0.39), while the risk ratio for having benefits was 1.93 (95% CI 1.90-1.94). Disease progression affects the financial situation of MS patients considerably. Correlations between higher disability and patient income were observed, suggesting that earnings and benefits could be used as measures of MS progression and proxies of disability.

INTENSITY AND GENERALIZATION OF TREADMILL-SLIP TRAINING: HIGH OR LOW; PROGRESSIVELY-INCREASE OR -DECREASE?

PubMed Central

Liu, Xuan; Bhatt, Tanvi; Pai, Yi-Chung (Clive)

2015-01-01

Very little is known how training intensity interacts with the generalization from treadmill-slip to overground slip. The purposes of this study were to determine whether treadmill-slip training improved center-of-mass stability, more so in the reactive than in the proactive control of stability, with high intensity (HI with a trial-to-trial-consistent acceleration of 12 m/s2) better than low intensity training (LO with a consistent acceleration of 6 m/s2), and progressively-increasing intensity (INCR with a block-to-block acceleration varied from 6 to 12 m/s2) better than progressively-decreasing intensity training (DECR with an acceleration varied from 12 to 6 m/s2) in such generalization. Thirty-six young subjects evenly assigned to one of four (HI, LO, INCR, DECR) groups underwent 24 treadmill-slips before their generalization test trial with a novel slip during overground walking. The controls (CTRL, n=9) from existing data only experienced the same novel overground slip without treadmill training but under otherwise identical condition. The results showed that treadmill-slip training did improved balance control on overground slip with a greater impact on subjects’ reactive (44.3%) than proactive control of stability (27.1%) in comparison to the CTRL. HI yielded stronger generalization than LO, while INCR was only marginally better than DECR. Finally, the group means of these four displayed a clear ascending order from CTRL, LO, DECR, INCR, to HI. The results suggested that higher training intensity on treadmill led to a better generalization, while a progressively-increase in intensity had advantage over the progressively-decrease or the low training strategy. (243 words) PMID:26159058

Can multiple sclerosis as a cognitive disorder influence patients’ dreams?

PubMed Central

Owji, Mahsa

2013-01-01

Dream should be considered as a kind of cognitive ability that is formed parallel to other cognitive capabilities like language. On the other hand, multiple sclerosis (MS) is a complex disease that can involve different aspects of our cognition. Therefore, MS may influence patients’ dreams. In fact, we do not know what the importance of dream is in MS, but further studies may introduce dream and dreaming as a sign of improvement or progression in MS disease. PMID:24250908

A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis.

PubMed

Hadjigeorgiou, G M; Doxani, C; Miligkos, M; Ziakas, P; Bakalos, G; Papadimitriou, D; Mprotsis, T; Grigoriadis, N; Zintzaras, E

2013-12-01

The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: 'patients free of relapse', 'patients without disease progression', 'patients without MRI progression' and 'patients with adverse events'. Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m(2)) using direct and indirect analyses. The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex ('patients free of relapse' and 'patients without MRI progression') and for Betaferon compared with Avonex ('patients without disease progression' and 'patients without MRI progression'). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: 'patients free of relapse' and 'patients without MRI progression'. Regarding 'patients with adverse events', no data were available for all comparisons to make fair inferences. This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments. © 2013 John Wiley & Sons Ltd.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

Systemic inflammation induces axon injury during brain inflammation.

PubMed

Moreno, Beatriz; Jukes, John-Paul; Vergara-Irigaray, Nuria; Errea, Oihana; Villoslada, Pablo; Perry, V Hugh; Newman, Tracey A

2011-12-01

Axon injury is a key contributor to the progression of disability in multiple sclerosis (MS). Systemic infections, which frequently precede relapses in MS, have been linked to clinical progression in Alzheimer's disease. There is evidence of a role for the innate immune system in MS lesions, as axonal injury is associated with macrophage activation. We hypothesize that systemic inflammation leads to enhanced axonal damage in MS as a consequence of innate immune system activation. Monophasic experimental allergic encephalomyelitis (EAE) was induced in a cohort of Lewis rats. The animals received a systemic challenge with either an inflammagen (lipopolysaccharide [LPS]) or saline as a control, at 1, 3, or 6 weeks into the remission phase of the disease. The clinical outcome, cellular recruitment to lesions, degree of tissue damage, and cytokine profiles were measured. We found that systemic inflammation activates the central nervous system (CNS) innate immune response and results in a switch in the macrophage/microglia phenotype. This switch was accompanied by inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) expression and increased axon injury. This increased injury occurred independently of the re-emergence of overt clinical signs. Our evidence indicates that microglia/macrophages, associated with lesions, respond to circulating cytokines, produced in response to an inflammatory event outside the CNS, by producing immune mediators that lead to tissue damage. This has implications for people with MS, in which prevention and stringent management of systemic infectious diseases may slow disease progression. Copyright © 2011 American Neurological Association.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

A longitudinal model for disease progression was developed and applied to multiple sclerosis

PubMed Central

Lawton, Michael; Tilling, Kate; Robertson, Neil; Tremlett, Helen; Zhu, Feng; Harding, Katharine; Oger, Joel; Ben-Shlomo, Yoav

2015-01-01

Objectives To develop a model of disease progression using multiple sclerosis (MS) as an exemplar. Study Design and Settings Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation. Results The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [−0.13 (95% CI: −0.39, 0.14), −0.15 (95% CI: −0.70, 0.40)] for BCMS and UoWMS, respectively. Conclusion It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced. PMID:26071892

Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation

PubMed Central

Starossom, Sarah C.; Veremeyko, Tatyana; Yung, Amanda W. Y.; Dukhinova, Marina; Au, Cheryl; Lau, Alexander Y.; Weiner, Howard L.; Ponomarev, Eugene D.

2015-01-01

Rationale Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases such as multiples sclerosis (MS) is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T cell differentiation towards pathogenic Th1/Th17 phenotypes are not completely understood. Objectives We investigated the role of platelets in the modulation of CD4 T cell functions in MS patients and in mice with experimental autoimmune encephalitis (EAE), an animal model for MS. Methods and Results We found that early in MS and EAE platelets degranulated and produced a number of soluble factors serotonin (5HT), PF4 and PAF, which specifically stimulated differentiation of T cells towards pathogenic Th1, Th17 and IFN-γ/IL-17-producing CD4 T cells. At the later stages of MS and EAE platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells, but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T cell aggregates involved interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T cell activation, proliferation and production of IFN-γ. Blocking of formation of platelet-CD4 T cell aggregates during progression of EAE substantially enhanced proliferation of CD4 T cell in the CNS and the periphery leading to exacerbation of the disease. Conclusion Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of CNS autoimmune inflammation. PMID:26294656

Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS

PubMed Central

Rocca, Maria A.; Leavitt, Victoria M.; Dackovic, Jelena; Mesaros, Sarlota; Drulovic, Jelena; DeLuca, John; Filippi, Massimo

2014-01-01

Objective: Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Methods: Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Results: Patients with MS declined in cognitive efficiency and memory (p < 0.001). MLBG moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline (p = 0.234, ηp2 = 0.039). Intellectual enrichment moderated decline in cognitive efficiency (p = 0.031, ηp2 = 0.126) and memory (p = 0.037, ηp2 = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. Conclusion: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with MS. PMID:24748670

Expiratory and phonation times as measures of disease severity in patients with Multiple Sclerosis. A case-control study.

PubMed

Nordio, Sara; Bernitsas, Evanthia; Meneghello, Francesca; Palmer, Katie; Stabile, Maria Rosaria; Dipietro, Laura; Di Stadio, Arianna

2018-04-21

Speech disorders are common in patients with Multiple Sclerosis (MS). They can be assessed with several methods, which are however expensive, complex, and not easily accessible to physicians during routine clinic visits. This study aimed at measuring maximum phonation times, maximum expiratory times, and articulation abilities scores in patients with MS compared to healthy subjects and at investigating if any of these parameters could be used as a measure of MS progression. 50 MS patients and 50 gender- and age-matched healthy controls were enrolled in the study. Maximum expiratory times and maximum phonation times were collected from both groups. Articulation abilities were evaluated using the articulation subtest from the Fussi assessment (dysarthria scores). MS patients were evaluated with the Expanded Disability Status Scale (EDSS). Correlations between EDSS scores and maximum expiratory times, maximum phonation times, and dysarthria scores were calculated. EDSS scores of MS patients ranged from 4.5 to 7.5. In MS patients, maximum expiratory times, maximum phonation times, and dysarthria scores were significantly altered compared to healthy controls. Moreover, the EDSS scores were correlated with the maximum expiratory times; the maximum expiratory times were correlated with the maximum phonation times, and the maximum phonation times were correlated with the dysarthria scores. As the expiratory times were significantly correlated with the EDSS scores, they could be used to measure the severity of MS and to monitor its progression. Copyright © 2018 Elsevier B.V. All rights reserved.

Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients.

PubMed

Garcia-Martin, Elena; Pueyo, Victoria; Almarcegui, Carmen; Martin, Jesus; Ara, Jose R; Sancho, Eva; Pablo, Luis E; Dolz, Isabel; Fernandez, Javier

2011-11-01

To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes.

Functional quantitative susceptibility mapping (fQSM).

PubMed

Balla, Dávid Z; Sanchez-Panchuelo, Rosa M; Wharton, Samuel J; Hagberg, Gisela E; Scheffler, Klaus; Francis, Susan T; Bowtell, Richard

2014-10-15

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is a powerful technique, typically based on the statistical analysis of the magnitude component of the complex time-series. Here, we additionally interrogated the phase data of the fMRI time-series and used quantitative susceptibility mapping (QSM) in order to investigate the potential of functional QSM (fQSM) relative to standard magnitude BOLD fMRI. High spatial resolution data (1mm isotropic) were acquired every 3 seconds using zoomed multi-slice gradient-echo EPI collected at 7 T in single orientation (SO) and multiple orientation (MO) experiments, the latter involving 4 repetitions with the subject's head rotated relative to B0. Statistical parametric maps (SPM) were reconstructed for magnitude, phase and QSM time-series and each was subjected to detailed analysis. Several fQSM pipelines were evaluated and compared based on the relative number of voxels that were coincidentally found to be significant in QSM and magnitude SPMs (common voxels). We found that sensitivity and spatial reliability of fQSM relative to the magnitude data depended strongly on the arbitrary significance threshold defining "activated" voxels in SPMs, and on the efficiency of spatio-temporal filtering of the phase time-series. Sensitivity and spatial reliability depended slightly on whether MO or SO fQSM was performed and on the QSM calculation approach used for SO data. Our results present the potential of fQSM as a quantitative method of mapping BOLD changes. We also critically discuss the technical challenges and issues linked to this intriguing new technique. Copyright © 2014 Elsevier Inc. All rights reserved.

Standardization in dimensional nanometrology: development of a calibration guideline for Scanning Probe Microscopy

NASA Astrophysics Data System (ADS)

Dziomba, Thorsten; Koenders, Ludger; Wilkening, Günter

2005-10-01

The continuing miniaturization in many technologies - among them the optical systems - demands high-resolution measurements with uncertainties in the nanometre-range or even well below. A brief introduction of measurement methods used at the micro- & nanometre scale is therefore given as introduction. While a wide range of these methods are well established for the determination of various physical properties down to the nanometric scale, it is Scanning Probe Microscopy (SPM) that provides a unique direct access to topographic surface features in the size range from atomic diameters to some ten or hundred micrometres. With the increasing use of SPMs as quantitative measurement instruments, the demand for standardized calibration routines also for this type of instruments rises. However, except for a few specially designed set-ups mainly at National Metrology Institutes (e. g. PTB in Germany), measurements made with SPMs usually lack traceability to the metre definition. A number of physical transfer standards have therefore been developed and are already available commercially. While detailed knowledge of the standards' properties is a prerequisite for their practical applicability, the calibration procedure itself deserves careful consideration as well. As there is, up to now, no generally accepted concept how to perform SPM calibrations, guidelines are now being developed on various national and international levels, e. g. VDI/VDE-GMA in Germany and ISO. This papers discusses the draft of an SPM calibration guideline by focusing on several critical practical aspects of SPM calibration. The paper intends to invite the readers to take active part in guideline discussions.

[Progress in the spectral library based protein identification strategy].

PubMed

Yu, Derui; Ma, Jie; Xie, Zengyan; Bai, Mingze; Zhu, Yunping; Shu, Kunxian

2018-04-25

Exponential growth of the mass spectrometry (MS) data is exhibited when the mass spectrometry-based proteomics has been developing rapidly. It is a great challenge to develop some quick, accurate and repeatable methods to identify peptides and proteins. Nowadays, the spectral library searching has become a mature strategy for tandem mass spectra based proteins identification in proteomics, which searches the experiment spectra against a collection of confidently identified MS/MS spectra that have been observed previously, and fully utilizes the abundance in the spectrum, peaks from non-canonical fragment ions, and other features. This review provides an overview of the implement of spectral library search strategy, and two key steps, spectral library construction and spectral library searching comprehensively, and discusses the progress and challenge of the library search strategy.

Biomarkers in the evolution of multiple sclerosis.

PubMed

Berger, Thomas

2017-11-01

Nonimaging biomarkers can be applied in differential diagnosis, evaluation of disease progression and therapy monitoring of multiple sclerosis (MS). Presence of oligoclonal IgG bands in cerebrospinal fluid is a diagnostic element and a negative predictor of MS evolution. AQP4 antibodies are pathogenic and diagnostic for neuromyelitis optica spectrum disorder. Antibodies to myelin oligodendrocyte glycoprotein develop in about 50% of predominantly pediatric patients with acute disseminated encephalomyelitis, but their possible role in pathogenesis is unknown. Currently, there are no individualized biomarkers suitable to track disease progression. Neutralizing antibodies against IFN-β, natalizumab and daclizumab arise with variable frequency and reduce treatment efficacy. The anti-John Cunningham virus antibody index has potential as a biomarker for risk of progressive multifocal leukoencephalopathy.

Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels

PubMed Central

Jukkola, Peter; Gu, Yuanzheng; Lovett-Racke, Amy E.; Gu, Chen

2017-01-01

The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults. PMID:29123469

Precision Medicine in Multiple Sclerosis: Future of PET Imaging of Inflammation and Reactive Astrocytes

PubMed Central

Poutiainen, Pekka; Jaronen, Merja; Quintana, Francisco J.; Brownell, Anna-Liisa

2016-01-01

Non-invasive molecular imaging techniques can enhance diagnosis to achieve successful treatment, as well as reveal underlying pathogenic mechanisms in disorders such as multiple sclerosis (MS). The cooperation of advanced multimodal imaging techniques and increased knowledge of the MS disease mechanism allows both monitoring of neuronal network and therapeutic outcome as well as the tools to discover novel therapeutic targets. Diverse imaging modalities provide reliable diagnostic and prognostic platforms to better achieve precision medicine. Traditionally, magnetic resonance imaging (MRI) has been considered the golden standard in MS research and diagnosis. However, positron emission tomography (PET) imaging can provide functional information of molecular biology in detail even prior to anatomic changes, allowing close follow up of disease progression and treatment response. The recent findings support three major neuroinflammation components in MS: astrogliosis, cytokine elevation, and significant changes in specific proteins, which offer a great variety of specific targets for imaging purposes. Regardless of the fact that imaging of astrocyte function is still a young field and in need for development of suitable imaging ligands, recent studies have shown that inflammation and astrocyte activation are related to progression of MS. MS is a complex disease, which requires understanding of disease mechanisms for successful treatment. PET is a precise non-invasive imaging method for biochemical functions and has potential to enhance early and accurate diagnosis for precision therapy of MS. In this review we focus on modulation of different receptor systems and inflammatory aspect of MS, especially on activation of glial cells, and summarize the recent findings of PET imaging in MS and present the most potent targets for new biomarkers with the main focus on experimental MS research. PMID:27695400

Clinical characteristics of patients with multiple sclerosis enrolled in a new registry in Egypt.

PubMed

Zakaria, Magd; Zamzam, Dina A; Abdel Hafeez, Mohamed A; Swelam, Mahmoud S; Khater, Shaimaa S; Fahmy, Mai F; Abdel Hady, Ayman; Fouad, Mohamed M; Abdel Nasser, Azza; Aref, Hany; Gadallah, Mohsen

2016-11-01

Epidemiological studies of multiple sclerosis (MS) are lacking in Egypt. To study the characteristics of Egyptian patients with multiple sclerosis in a new registry in a major tertiary referral centre in Cairo, Egypt. Patients were from the project MS database of the Multiple Sclerosis Unit at Ain Shams University Hospitals (N=950). We conducted a detailed medical history and examination including the Expanded Disability Status Scale (EDSS). Females represented 72% of subjects (female: male ratio 2.57:1). The mean age of disease onset was 26.1±7.6 years. Relapsing-remitting MS (RRMS) was the most common presentation (74.6%). Visual or sensory symptoms were the most common at presentation with RRMS, while motor symptoms were the most common presentation in other types of MS. Time to diagnosis was delayed up to 2 years in 27.8% of patients. The mean EDSS score was 3.6±2.1; 55% had EDSS≤3. About half (49%) received a disease-modifying drug. Progressive MS and motor presentation were associated with higher disability. This is the first documented MS registry from Egypt. The clinical characteristics of MS in Egypt was similar to other Arab countries and western countries. MS is more common among females in Egypt, with RRMS being the most common presentation. Visual symptoms and motor symptoms were the most common presentations in RRMS and progressive MS, respectively. Our findings also highlight the value of establishing registries in Egypt in order to be able to study, prospectively, the clinical course of the disease, the response to various DMD's and the epidemiology of MS in Egypt. Copyright © 2016 Elsevier B.V. All rights reserved.

Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease.

PubMed

Dunn, Shannon E; Gunde, Eva; Lee, Hyunwoo

2015-01-01

It is well known that a number of autoimmune diseases including multiple sclerosis (MS) predominantly affect women and there has been much attention directed toward understanding why this is the case. Past research has revealed a number of sex differences in autoimmune responses that can account for the female bias in MS. However, much less is known about why the incidence of MS has increased exclusively in women over the past half century. The recency of this increase suggests that changing environmental or lifestyle factors are interacting with biological sex to increase MS risk predominantly in females. Indeed, a number of recent studies have identified sex-specific differences in the effect of environmental factors on MS incidence. The first part of this chapter will overview this evidence and will discuss the possible scenarios of how the environment may be interacting with autoimmune mechanisms to contribute to the preferential rise in MS incidence in women. Despite the strong female bias in MS incidence, culminating evidence from natural history studies, and imaging and pathology studies suggests that males who develop MS may exhibit a more rapid decline in disability and cognitive functioning than women. Very little is known about the biological basis of this more rapid deterioration, but some insights have been provided by studies in rodent models of demyelination/remyelination. The second part of this chapter will overview the evidence that males with relapsing-onset MS undergo a more rapid progression of disease than females and will discuss potential biological mechanisms that account for this sex difference.

MS/MS library facilitated MRM quantification of native peptides prepared by denaturing ultrafiltration

PubMed Central

2012-01-01

Naturally occurring native peptides provide important information about physiological states of an organism and its changes in disease conditions but protocols and methods for assessing their abundance are not well-developed. In this paper, we describe a simple procedure for the quantification of non-tryptic peptides in body fluids. The workflow includes an enrichment step followed by two-dimensional fractionation of native peptides and MS/MS data management facilitating the design and validation of LC- MRM MS assays. The added value of the workflow is demonstrated in the development of a triplex LC-MRM MS assay used for quantification of peptides potentially associated with the progression of liver disease to hepatocellular carcinoma. PMID:22304756

Thalamic lesions in multiple sclerosis by 7T MRI: Clinical implications and relationship to cortical pathology.

PubMed

Harrison, Daniel M; Oh, Jiwon; Roy, Snehashis; Wood, Emily T; Whetstone, Anna; Seigo, Michaela A; Jones, Craig K; Pham, Dzung; van Zijl, Peter; Reich, Daniel S; Calabresi, Peter A

2015-08-01

Pathology in both cortex and deep gray matter contribute to disability in multiple sclerosis (MS). We used the increased signal-to-noise ratio of 7-tesla (7T) MRI to visualize small lesions within the thalamus and to relate this to clinical information and cortical lesions. We obtained 7T MRI scans on 34 MS cases and 15 healthy volunteers. Thalamic lesion number and volume were related to demographic data, clinical disability measures, and lesions in cortical gray matter. Thalamic lesions were found in 24/34 of MS cases. Two lesion subtypes were noted: discrete, ovoid lesions, and more diffuse lesional areas lining the periventricular surface. The number of thalamic lesions was greater in progressive MS compared to relapsing-remitting (mean ±SD, 10.7 ±0.7 vs. 3.0 ±0.7, respectively, p < 0.001). Thalamic lesion burden (count and volume) correlated with EDSS score and measures of cortical lesion burden, but not with white matter lesion burden or white matter volume. Using 7T MRI allows identification of thalamic lesions in MS, which are associated with disability, progressive disease, and cortical lesions. Thalamic lesion analysis may be a simpler, more rapid estimate of overall gray matter lesion burden in MS. © The Author(s), 2015.

A study of insulin resistance by HOMA-IR and its cut-off value to identify metabolic syndrome in urban Indian adolescents.

PubMed

Singh, Yashpal; Garg, M K; Tandon, Nikhil; Marwaha, Raman Kumar

2013-01-01

Insulin resistance (IR) and associated metabolic abnormalities are increasingly being reported in the adolescent population. Cut-off value of homeostasis model of assessment IR (HOMA-IR) as an indicator of metabolic syndrome (MS) in adolescents has not been established. This study aimed to investigate IR by HOMA-IR in urban Indian adolescents and to establish cut-off values of HOMA-IR for defining MS. A total of 691 apparently healthy adolescents (295 with normal body mass index (BMI), 205 overweight, and 199 obese) were included in this cross-sectional study. MS in adolescents was defined by International Diabetes Federation (IDF) and Adult Treatment Panel III (ATP III) criteria. IR was calculated using the HOMA model. Mean height, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and blood pressure were significantly higher in boys as compared to girls. The HOMA-IR values increased progressively from normal weight to obese adolescents in both sexes. Mean HOMA-IR values increased progressively according to sexual maturity rating in both sexes. HOMA-IR value of 2.5 had a sensitivity of >70% and specificity of >60% for MS. This cut-off identified larger number of adolescents with MS in different BMI categories (19.7% in normal weight, 51.7% in overweight, and 77.0% in obese subjects) as compared to the use of IDF or ATP III criteria for diagnosing MS. Odds ratio for having IR (HOMA-IR of >2.5) was highest with WHtR (4.9, p p<0.0001) and WC (4.8, p p<0.0001), compared to WHR (3.3, p p<0.0001). In Indian adolescents, HOMA-IR increased with sexual maturity and with progression from normal to obese. A HOMA-IR cut-off of 2.5 provided the maximum sensitivity and specificity in diagnosing MS in both genders as per ATP III and IDF criteria.

A Study of Insulin Resistance by HOMA-IR and its Cut-off Value to Identify Metabolic Syndrome in Urban Indian Adolescents

PubMed Central

Singh, Yashpal; Garg, MK; Tandon, Nikhil; Marwaha, Raman Kumar

2013-01-01

Objective: Insulin resistance (IR) and associated metabolic abnormalities are increasingly being reported in the adolescent population. Cut-off value of homeostasis model of assessment IR (HOMA-IR) as an indicator of metabolic syndrome (MS) in adolescents has not been established. This study aimed to investigate IR by HOMA-IR in urban Indian adolescents and to establish cut-off values of HOMA-IR for defining MS. Methods: A total of 691 apparently healthy adolescents (295 with normal body mass index (BMI), 205 overweight, and 199 obese) were included in this cross-sectional study. MS in adolescents was defined by International Diabetes Federation (IDF) and Adult Treatment Panel III (ATP III) criteria. IR was calculated using the HOMA model. Results: Mean height, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and blood pressure were significantly higher in boys as compared to girls. The HOMA-IR values increased progressively from normal weight to obese adolescents in both sexes. Mean HOMA-IR values increased progressively according to sexual maturity rating in both sexes. HOMA-IR value of 2.5 had a sensitivity of >70% and specificity of >60% for MS. This cut-off identified larger number of adolescents with MS in different BMI categories (19.7% in normal weight, 51.7% in overweight, and 77.0% in obese subjects) as compared to the use of IDF or ATP III criteria for diagnosing MS. Odds ratio for having IR (HOMA-IR of >2.5) was highest with WHtR (4.9, p <0.0001) and WC (4.8, p <0.0001), compared to WHR (3.3, p <0.0001). Conclusions: In Indian adolescents, HOMA-IR increased with sexual maturity and with progression from normal to obese. A HOMA-IR cut-off of 2.5 provided the maximum sensitivity and specificity in diagnosing MS in both genders as per ATP III and IDF criteria. Conflict of interest:None declared. PMID:24379034

The effectiveness of Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressIve MultiplE sclerosis patients (RAGTIME): study protocol for a randomized controlled trial.

PubMed

Straudi, Sofia; Manfredini, Fabio; Lamberti, Nicola; Zamboni, Paolo; Bernardi, Francesco; Marchetti, Giovanna; Pinton, Paolo; Bonora, Massimo; Secchiero, Paola; Tisato, Veronica; Volpato, Stefano; Basaglia, Nino

2017-02-27

Gait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and (2) to explore changes of clinical and circulating biomarkers of neural plasticity. This will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6-7) will be randomly assigned to receive twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed, body weight support) are set during the first session and progressively adjusted during training progression or (2) individual conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The same assessors will perform outcome measurements at four time points: baseline (before the first intervention session); intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after 3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and metabolic parameters). The RAGT training is expected to improve mobility compared to the active control intervention in progressive MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes. ClinicalTrials.gov, identifier: NCT02421731 . Registered on 19 January 2015 (retrospectively registered).

Improving quality of life in multiple sclerosis: an unmet need.

PubMed

Zwibel, Howard L; Smrtka, Jennifer

2011-05-01

Multiple sclerosis (MS) affects approximately 400,000 people in the United States and 2.1 million people worldwide. It is the most common chronic, non-traumatic neurological disorder afflicting young people during their peak productive ages. MS can diminish quality of life (QOL) by interfering with the ability to work, pursue leisure activities, and carry on usual life roles. Symptoms that affect QOL may include impaired mobility, fatigue, depression, pain, spasticity, cognitive impairment, sexual dysfunction, bowel and bladder dysfunction, vision and hearing problems, seizures, and sDwallowing and breathing difficulties. Direct medical costs of MS in the United States are estimated in excess of $10 billion per year. Indirect costs of MS include costs of reduced employment or unemployment, assistive equipment, disability related home modifications, and paid and unpaid personal care. Although direct medical costs predominate in the earlier stages of MS, indirect costs of productivity loss are responsible for higher costs later. Disease-modifying therapies (DMTs) lessen symptoms, reduce relapses, and delay disability progression. Unfortunately, many DMTs might produce only modest improvements in QOL. Although symptom-specific therapies do not delay disease progression, they may delay unemployment and dependency, thereby reducing indirect costs.

The Dress: Transforming a web viral event into a scientific survey.

PubMed

Moccia, Marcello; Lavorgna, Luigi; Lanzillo, Roberta; Brescia Morra, Vincenzo; Tedeschi, Gioacchino; Bonavita, Simona

2016-05-01

The Dress picture recently has become a hot topic on the Internet, prompting a debate whether it was black and blue, or white and gold. To investigate The Dress color perception in both multiple sclerosis (MS) patients, characterized by frequent visual system impairment with ensuing color vision effects, and general population. We developed a questionnaire to record demographics, clinical features, and The Dress color perception, posted on general and MS-specific social networks. No statistically significant differences were observed in The Dress color perception between MS patients (n=103) and general population (n=441). Furthermore, white and gold color perception was positively associated with aging in the general population (p=0.04), whereas negatively associated with progressive course (p=0.03) and longer disease duration (p<0.001) in MS patients, independently from patients' age. The Dress black and blue or white and gold perception might be due to aging in the general population, whereas black and blue perception, despite of aging, might suggest a specific effect of the MS burden (i.e. disease duration and progression) on the visual structures specifically involved in the white and gold perception. Copyright © 2016 Elsevier B.V. All rights reserved.

Demographic and clinical profile of Multiple Sclerosis in Kashmir: A short report.

PubMed

Zahoor, Insha; Asimi, Ravouf; Haq, Ehtishamul; Yousuf Wani, Irfan

2017-04-01

Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system (CNS). There have been only few population/hospital based studies on MS in India, and at the same time there is no data on its profile in Kashmir. A total of 41 MS patients diagnosed on the basis of 2010 Revised Mc Donald criteria were enrolled in this study from Kashmir region of India. Clinical, demographic, radiological and biochemical parameters were analyzed for most of the patients. Male to female ratio was found to be 1:3.1 with mean age at the time of analysis 32.26±7.54 (range 18-48) years. The mean disease duration was found to be 3.2±3.6 years. The most common course was relapsing-remitting (RR) present in 87.80% of cases followed by secondary progressive (SP) in 9.76% and primary progressive (PP) in 2.44%. Numbness, weakness of limbs, prickling and tingling sensations, muscle stiffness, and visual disturbances were most common manifestations. Condition of bilateral internuclear ophthalmoplegia (INO) and vertigo was rarely observed. Oligoclonal bands (OCB) were present in cerebrospinal fluid (CSF) of majority of the patients. Symptomatic and steroidal treatment mode was given to majority of the patients (92.68%) and only 7.32% patients were given disease modifying drug. This is the first preliminary report on MS profile in Kashmir. The high prevalence of female patients and RR course of MS, low prevalence of progressive cases, predominance of OCB positive cases, insignificant family history in all cases, predominance of cases with low socio-economic status, and high rate of less educated and unemployed cases are the most important findings. By and large MS pattern in Kashmir was found to be relatively similar to West and rest of the Asia. Larger comprehensive studies are mandatory to completely understand MS pattern in Kashmir. There is utmost requirement to maintain a local MS registry in Kashmir so as to get an idea about the actual number of persons suffering from the disease and compare the data with other regions of India. Copyright © 2017 Elsevier B.V. All rights reserved.

Relapse May Serve as a Mediator Variable in Longitudinal Outcomes in Multiple Sclerosis.

PubMed

Stone, Lael Anne; Cutter, Gary Raymond; Fisher, Elizabeth; Richert, Nancy; McCartin, Jennifer; Ohayon, Joan; Bash, Craig; McFarland, Henry

2016-05-01

Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years. Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated. While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS. While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that 1 route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted. Copyright © 2015 by the American Society of Neuroimaging.

The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

PubMed

Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

2016-09-01

Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

The state of multiple sclerosis: current insight into the patient/health care provider relationship, treatment challenges, and satisfaction.

PubMed

Tintoré, Mar; Alexander, Maggie; Costello, Kathleen; Duddy, Martin; Jones, David E; Law, Nancy; O'Neill, Gilmore; Uccelli, Antonio; Weissert, Robert; Wray, Sibyl

2017-01-01

Managing multiple sclerosis (MS) treatment presents challenges for both patients and health care professionals. Effective communication between patients with MS and their neurologist is important for improving clinical outcomes and quality of life. A closed-ended online market research survey was used to assess the current state of MS care from the perspective of both patients with MS (≥18 years of age) and neurologists who treat MS from Europe and the US and to gain insight into perceptions of treatment expectations/goals, treatment decisions, treatment challenges, communication, and satisfaction with care, based on current clinical practice. A total of 900 neurologists and 982 patients completed the survey, of whom 46% self-identified as having remitting-relapsing MS, 29% secondary progressive MS, and 11% primary progressive MS. Overall, patients felt satisfied with their disease-modifying therapy (DMT); satisfaction related to comfort in speaking with their neurologist and participation in their DMT decision-making process. Patients who self-identified as having relapsing-remitting MS were more likely to be very satisfied with their treatment. Top challenges identified by patients in managing their DMT were cost, side effects/tolerability of treatment, and uncertainty if treatment was working. Half of the patients reported skipping doses, but only 68% told their health care provider that they did so. Several important differences in perception were identified between patients and neurologists concerning treatment selection, satisfaction, expectations, goals, and comfort discussing symptoms, as well as treatment challenges and skipped doses. The study results emphasize that patient/neurologist communication and patient input into the treatment decision-making process likely influence patient satisfaction with treatment.

Increasing the throughput and productivity of Caco-2 cell permeability assays using liquid chromatography-mass spectrometry: application to resveratrol absorption and metabolism.

PubMed

Li, Yongmei; Shin, Young Geun; Yu, Chongwoo; Kosmeder, Jerome W; Hirschelman, Wendy H; Pezzuto, John M; van Breemen, Richard B

2003-12-01

The Caco-2 cell monolayer permeability assay has become a standard model of human intestinal absorption and transport. This paper reviews recent progress in increasing the throughput of Caco-2 cell monolayer assays and in expanding the scope of this assay to include modeling intestinal drug metabolism. The state-of-the-art in Caco-2 cell monolayer permeability assays combines multi-well plates fitted with semi-permeable inserts on which Caco-2 cells have been cultured with liquid chromatography-mass spectrometry (LC-MS) or LC-tandem mass spectrometry (LC-MS-MS) for the quantitative analysis of test compounds and the identification of their intestinal metabolites. After reviewing the progress in increasing the throughput of Caco-2 cell monolayer assays for both modeling human intestinal permeability or transport and the metabolism of xenobiotic compounds, we demonstrate the application of LC-MS and LC-MS-MS to the measurement of resveratrol permeability and metabolism in the Caco-2 model. trans-Resveratrol (trans-3,5,4'-trihydroxystilbene) is a polyphenolic compound occurring in grapes, peanuts and other food sources, that is under investigation as a cancer chemoprevention agent. The apparent permeability coefficient for apical (AP) to basolateral (BL) movement of resveratrol was 2.0 x 10(-5)cm/sec. Resveratrol was not a substrate for P-glycoprotein or the multi-drug resistance associated proteins (MRP). No phase I metabolites were observed, but the phase II conjugates resveratrol-3-glucuronide and resveratrol-3-sulfate was identified based on LC-MS and LC-MS-MS analysis and comparison with synthetic standards. Although these data indicate that resveratrol diffuses rapidly across the intestinal epithelium, extensive phase II metabolism during absorption might reduce resveratrol bioavailability.

Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions

PubMed Central

Mehta, Veela; Pei, Wei; Yang, Grant; Li, Suyang; Swamy, Eashwar; Boster, Aaron; Schmalbrock, Petra; Pitt, David

2013-01-01

MRI phase imaging in multiple sclerosis (MS) patients and in autopsy tissue have demonstrated the presence of iron depositions in white matter lesions. The accumulation of iron in some but not all lesions suggests a specific, potentially disease-relevant process, however; its pathophysiological significance remains unknown. Here, we explore the role of lesional iron in multiple sclerosis using multiple approaches: immunohistochemical examination of autoptic MS tissue, an in vitro model of iron-uptake in human cultured macrophages and ultra-highfield phase imaging of highly active and of secondary progressive MS patients. Using Perls' stain and immunohistochemistry, iron was detected in MS tissue sections predominantly in non-phagocytosing macrophages/microglia at the edge of established, demyelinated lesions. Moreover, iron-containing macrophages but not myelin-laden macrophages expressed markers of proinflammatory (M1) polarization. Similarly, in human macrophage cultures, iron was preferentially taken up by non-phagocytosing, M1-polarized macrophages and induced M1 (super) polarization. Iron uptake was minimal in myelin-laden macrophages and active myelin phagocytosis led to depletion of intracellular iron. Finally, we demonstrated in MS patients using GRE phase imaging with ultra-highfield MRI that phase hypointense lesions were significantly more prevalent in patients with active relapsing than with secondary progressive MS. Taken together, our data provide a basis to interpret iron-sensitive GRE phase imaging in MS patients: iron is present in non-phagocytosing, M1-polarized microglia/macrophages at the rim of chronic active white matter demyelinating lesions. Phase imaging may therefore visualize specific, chronic proinflammatory activity in established MS lesions and thus provide important clinical information on disease status and treatment efficacy in MS patients. PMID:23516409

The state of multiple sclerosis: current insight into the patient/health care provider relationship, treatment challenges, and satisfaction

PubMed Central

Tintoré, Mar; Alexander, Maggie; Costello, Kathleen; Duddy, Martin; Jones, David E; Law, Nancy; O’Neill, Gilmore; Uccelli, Antonio; Weissert, Robert; Wray, Sibyl

2017-01-01

Background Managing multiple sclerosis (MS) treatment presents challenges for both patients and health care professionals. Effective communication between patients with MS and their neurologist is important for improving clinical outcomes and quality of life. Methods A closed-ended online market research survey was used to assess the current state of MS care from the perspective of both patients with MS (≥18 years of age) and neurologists who treat MS from Europe and the US and to gain insight into perceptions of treatment expectations/goals, treatment decisions, treatment challenges, communication, and satisfaction with care, based on current clinical practice. Results A total of 900 neurologists and 982 patients completed the survey, of whom 46% self-identified as having remitting-relapsing MS, 29% secondary progressive MS, and 11% primary progressive MS. Overall, patients felt satisfied with their disease-modifying therapy (DMT); satisfaction related to comfort in speaking with their neurologist and participation in their DMT decision-making process. Patients who self-identified as having relapsing-remitting MS were more likely to be very satisfied with their treatment. Top challenges identified by patients in managing their DMT were cost, side effects/tolerability of treatment, and uncertainty if treatment was working. Half of the patients reported skipping doses, but only 68% told their health care provider that they did so. Conclusion Several important differences in perception were identified between patients and neurologists concerning treatment selection, satisfaction, expectations, goals, and comfort discussing symptoms, as well as treatment challenges and skipped doses. The study results emphasize that patient/neurologist communication and patient input into the treatment decision-making process likely influence patient satisfaction with treatment. PMID:28053511

Cardiac effects of mitoxanthrone therapy in patients with multiple sclerosis.

PubMed

Pastuszak, Żanna; Tomczykiewicz, Kazimierz; Piusińska-Macoch, Renata; Stępień, Adam

2016-01-01

Mitoxanthrone (MTX) is a synthetic anthracycline antibiotic that has been used for several years in the treatment of patients with primary progressive, secondary progressive, and relapsing remitting multiple sclerosis (MS) who do not respond to other drugs. MTX has antineoplastic, immunomodulatory, and antibacterial properties. The most common adverse effects of MTX include nausea and vomiting, hair loss, increased risk of urinary and respiratory tract infections, and amenorrhea. Less frequent problems include leukopenia, thrombocytopenia, anaemia, and an increase in hepatic enzyme and bilirubin levels. Other severe sequelae of MTX treatment are drug cardiotoxicity and a potential to induce leukaemia. Drug toxicity results from its affinity to iron ions. The resulting complex strongly induces formation of free oxygen radicals and increases lipid peroxidation. Asymptomatic reduction in left ventricular ejection fraction (LVEF) by two-dimensional (2D) echocardiography, cardiomyopathy, and congestive heart failure have been observed in patients with MS at a rate of about 2.6-5%. Few studies evaluated cardiotoxicity of MTX in MS patients. Most previous studies were performed in small groups of cancer patients and cardiac evaluation was limited to physical examination. To evaluate the effect of MTX treatment on LVEF by 2D echocardiography. We studied 72 MS patients aged 25-63 years who were treated with MTX in 2002-2014. The diagnosis of MS was made using the 2001 McDonald criteria updated in 2005. The study group included primary progressive MS in 40 (56%) patients, secondary progressive MS in 5 (7%) patients, and relapsing remitting MS in 27 (37%) patients. MTX was administered at 12 mg/m2 of body surface area every 3 months (up to the total dose of 140 mg/m2). MTX treatment was initiated in patients with no signs of heart failure on physical examination, normal electrocardiogram (ECG), normal LVEF by 2D echocardiography, and normal laboratory test findings including complete blood count and hepatic and renal function parameters. Each MTX administration was preceded by 2D echocardiography with LVEF measurement, ECG, and physical examination of the cardiovascular system. The effect of MTX treatment on LVEF was evaluated by comparing baseline LVEF with LVEF measurements before the last MTX dose. Statistical analysis was performed using the Student t test. The mean LVEF before administration of the first MTX dose was 65 ± 3.3%. The lowest LVEF at the final 2D echo-cardiographic examination was 60 ± 2.1%. We did not find a significant LVEF reduction during MTX treatment in MS patients compared to baseline values. Severe myocardial dysfunction manifesting with significant LVEF reduction by 2D echocardiography or clinical evidence of heart failure was not noted in any patient in the study group. Our study showed no significant LVEF reduction during MTX monotherapy in MS patients without a history of a cardiac disease and with normal echocardiographic findings at baseline. Long-term cardiac effects of MTX require further studies.

A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?

PubMed

Perwein, Maria K; Smestad, John A; Warrington, Arthur E; Heider, Robin M; Kaczor, Mark W; Maher, Louis J; Wootla, Bharath; Kunbaz, Ahmad; Rodriguez, Moses

2018-05-01

Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions. Areas covered: We discuss the history and development of natural human IgM-isotype immunoglobulins (HIgMs) and recently-identified aptamer-conjugates that have been shown to enhance endogenous myelin repair in animal models of demyelination by acting on myelin-producing oligodendrocytes (OLs) or oligodendrocyte progenitor cells (OPCs) within CNS lesions. We also discuss future development aims and applications for these important novel technologies. Expert opinion: Aptamer conjugate Myaptavin-3064 and recombinant human IgM-isotype antibody rHIgM22 regenerate CNS myelin, thereby reducing axonal degeneration and offering the potential of recovery from MS relapses, reversal of disability and prevention of disease progression. Advancement of these technologies into the clinic for MS treatment is therefore a top priority. It remains unclear to what extent the therapeutic modalities of remyelinating antibodies and aptamers may synergize with other currently-approved therapies to yield enhanced therapeutic effects.

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression.

PubMed

Moccia, Marcello; Lanzillo, Roberta; Palladino, Raffaele; Chang, Kiara Chu-Mei; Costabile, Teresa; Russo, Cinzia; De Rosa, Anna; Carotenuto, Antonio; Saccà, Francesco; Maniscalco, Giorgia Teresa; Brescia Morra, Vincenzo

2016-04-01

Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing-remitting (RR). To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS. © The Author(s), 2015.

A qualitative study assessing patient perspectives in the process of decision-making on disease modifying therapies (DMT's) in multiple sclerosis (MS).

PubMed

Ceuninck van Capelle, Archibald de; Meide, Hanneke van der; Vosman, Frans J H; Visser, Leo H

2017-01-01

Physicians commonly advise patients to begin disease modifying therapies (DMT's) shortly after the establishment of a diagnosis of Multiple Sclerosis (MS) to prevent further relapses and disease progression. However, little is known about the meaning for patients going through the process of the diagnosis of MS and of making decisions on DMT's in early MS. To explore the patient perspective on using DMT's for MS. Methods: Ten participants with a recent (< 2 years) relapsing-remitting MS diagnosis were interviewed. Seven of them were using DMT's at the time of the interview. All interviews were transcribed and analyzed using a hermeneutical-phenomenological approach. The analysis revealed the following themes: (1) Constant confrontation with the disease, (2) Managing inevitable decline, (3) Hope of delaying the progression of the disease, and, (4) The importance of social support. The themes show that patients associate the recommendation to begin DMT's (especially injectable DMT's) with views about their bodies as well as their hopes about the future. Both considering and adhering to treatment are experienced by patients as not only matters of individual and rational deliberation, but also as activities that are lived within a web of relationships with relatives and friends. From the patient perspective, the use of DMT's is not a purely rational and individual experience. More attention to the use of DMT's as relational and lived phenomena will improve the understanding of the process of decision-making for DMT's in MS.

Inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS for isotope analysis of long-lived radionuclides

NASA Astrophysics Data System (ADS)

Becker, J. Sabine

2005-04-01

For a few years now inductively coupled plasma mass spectrometry has been increasingly used for precise and accurate determination of isotope ratios of long-lived radionuclides at the trace and ultratrace level due to its excellent sensitivity, good precision and accuracy. At present, ICP-MS and also laser ablation ICP-MS are applied as powerful analytical techniques in different fields such as the characterization of nuclear materials, recycled and by-products (e.g., spent nuclear fuel or depleted uranium ammunitions), radioactive waste control, in environmental monitoring and in bioassay measurements, in health control, in geochemistry and geochronology. Especially double-focusing sector field ICP mass spectrometers with single ion detector or with multiple ion collector device have been used for the precise determination of long-lived radionuclides isotope ratios at very low concentration levels. Progress has been achieved by the combination of ultrasensitive mass spectrometric techniques with effective separation and enrichment procedures in order to improve detection limits or by the introduction of the collision cell in ICP-MS for reducing disturbing interfering ions (e.g., of 129Xe+ for the determination of 129I). This review describes the state of the art and the progress of ICP-MS and laser ablation ICP-MS for isotope ratio measurements of long-lived radionuclides in different sample types, especially in the main application fields of characterization of nuclear and radioactive waste material, environmental research and health controls.

Association among metabolic syndrome, inflammation, and survival in prostate cancer.

PubMed

Conteduca, Vincenza; Caffo, Orazio; Galli, Luca; Maugeri, Antonio; Scarpi, Emanuela; Maines, Francesca; Chiuri, Vincenzo Emanuele; Lolli, Cristian; Kinspergher, Stefania; Schepisi, Giuseppe; Santoni, Matteo; Santini, Daniele; Fratino, Lucia; Burgio, Salvatore Luca; Salvi, Samanta; Menna, Cecilia; De Giorgi, Ugo

2018-05-01

Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016. MS was defined by modified adult treatment panel-III criteria. INF was characterized by at least one of these criteria: neutrophil to lymphocyte ratio ≥ 3, elevated erythrocyte sedimentation rate or C-reactive protein. Eighty-three of 551 (15.1%) patients met MS criteria at baseline and 34 (6.2%) during treatment. MS patients (MS+) presented a greater INF profile compared to MS- (P<0.0001). Median PFS was 3.7 for MS+ vs. 8.7 months for MS- (hazard ratio [HR] = 2.77; 95% CI: 2.12-3.61; P<0.0001). Median OS was 6.9 and 19 months in MS+ and MS-, respectively (HR = 3.43; 95% CI: 2.56-4.58; P<0.0001). We also demonstrated INF led to shorter PFS and OS (4.5 vs. 8.5 months, HR = 1.48, 95% CI: 1.15-1.90, P = 0.002, and 11.2 vs. 18.8 months, HR =1.66, 95% CI: 1.26-2.18, P = 0.0003, respectively). The combination of MS with INF provided the identification of high-risk prognostic group (MS+/INF+ vs. MS-/INF-) with worse PFS (3.7 vs. 9 months, HR = 2.7, 95% CI: 1.88-3.89, P<0.0001) and OS (6.3 vs. 20.4 months, HR = 4.04, 95% CI: 2.75-5.93, P<0.0001). Multivariable analysis confirmed that MS was independently associated with PFS (HR = 2.07; 95% CI: 1.03-4.18; P = 0.041) and OS (HR = 4.87; 95% CI: 2.36-10.03; P<0.0001). The absence of INF as an independent predictor of survival underlined the correlation between MS/INF. Pretreatment identification of MS and INF alterations might represent an available and easy tool for better prognostication of patients with mCRPC. A prospective evaluation is warranted. Copyright © 2018 Elsevier Inc. All rights reserved.

Persistent visual impairment in multiple sclerosis: prevalence, mechanisms and resulting disability.

PubMed

Jasse, Laurence; Vukusic, Sandra; Durand-Dubief, Françoise; Vartin, Cristina; Piras, Carolina; Bernard, Martine; Pélisson, Denis; Confavreux, Christian; Vighetto, Alain; Tilikete, Caroline

2013-10-01

The objective of this article is to evaluate in multiple sclerosis (MS) patients the prevalence of persistent complaints of visual disturbances and the mechanisms and resulting functional disability of persistent visual complaints (PVCs). Firstly, the prevalence of PVCs was calculated in 303 MS patients. MS-related data of patients with or without PVCs were compared. Secondly, 70 patients with PVCs performed an extensive neuro-ophthalmologic assessment and a vision-related quality of life questionnaire, the National Eye Institute Visual Functionary Questionnaire (NEI-VFQ-25). PVCs were reported in 105 MS patients (34.6%). Patients with PVCs had more frequently primary progressive MS (30.5% vs 13.6%) and more neuro-ophthalmologic relapses (1.97 vs 1.36) than patients without PVCs. In the mechanisms/disability study, an afferent visual and an ocular-motor pathways dysfunction were respectively diagnosed in 41 and 59 patients, mostly related to bilateral optic neuropathy and bilateral internuclear ophthalmoplegia. The NEI-VFQ 25 score was poor and significantly correlated with the number of impaired neuro-ophthalmologic tests. Our study emphasizes the high prevalence of PVC in MS patients. Regarding the nature of neuro-ophthalmologic deficit, our results suggest that persistent optic neuropathy, as part of the progressive evolution of the disease, is not rare. We also demonstrate that isolated ocular motor dysfunctions induce visual disability in daily life.

Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.

PubMed

Hofstetter, Louis; Naegelin, Yvonne; Filli, Lukas; Kuster, Pascal; Traud, Stefan; Smieskova, Renata; Mueller-Lenke, Nicole; Kappos, Ludwig; Gass, Achim; Sprenger, Till; Penner, Iris-Katharina; Nichols, Thomas E; Vrenken, Hugo; Barkhof, Frederik; Polman, Chris; Radue, Ernst-Wilhelm; Borgwardt, Stefan J; Bendfeldt, Kerstin

2014-02-01

In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. The aim of this study was to compare regional GM volume changes in relapsing-remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y(-1)) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y(-1) in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all P(corrected) < 0.05). These results suggested a direct association of disability progression and regional GM atrophy in RRMS.

Cognitive Impairment in MS Linked to Structural and Functional Connectivity

DTIC Science & Technology

2015-10-01

DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is...Requirements………………………………… 9 9. Appendices……………………………………………………………9 Krupp MS130103  2    Abstract Multiple sclerosis (MS) is the most common progressive...information processing needed to learn and solve problems. This symptom represents a major concern for many individuals living with multiple sclerosis

Single nucleotide polymorphisms in multiple sclerosis: disease susceptibility and treatment response biomarkers.

PubMed

Pravica, Vera; Popadic, Dusan; Savic, Emina; Markovic, Milos; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2012-04-01

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by unpredictable and variable clinical course. Etiology of MS involves both genetic and environmental factors. New technologies identified genetic polymorphisms associated with MS susceptibility among which immunologically relevant genes are significantly overrepresented. Although individual genes contribute only a small part to MS susceptibility, they might be used as biomarkers, thus helping to identify accurate diagnosis, predict clinical disease course and response to therapy. This review focuses on recent progress in research on MS genetics with special emphasis on the possibility to use single nucleotide polymorphism of candidate genes as biomarkers of susceptibility to disease and response to therapy.

Personalized medicine in multiple sclerosis.

PubMed

Giovannoni, Gavin

2017-11-01

The therapeutic approach in multiple sclerosis (MS) requires a personalized medicine frame beyond the precision medicine concept, which is not currently implementable due to the lack of robust biomarkers and detailed understanding of MS pathogenesis. Personalized medicine demands a patient-focused approach, with disease taxonomy informed by characterization of pathophysiological processes. Important questions concerning MS taxonomy are: when does MS begin? When does the progressive phase begin? Is MS really two or three diseases? Does a therapeutic window truly exist? Newer evidence points to a disease spectrum and a therapeutic lag of several years for benefits to be observed from disease-modifying therapy. For personalized treatment, it is important to ascertain disease stage and any worsening of focal inflammatory lesions over time.

Multiple Sclerosis and Employment: A Research Review Based on the International Classification of Function

ERIC Educational Resources Information Center

Frain, Michael P.; Bishop, Malachy; Rumrill, Phillip D., Jr.; Chan, Fong; Tansey, Timothy N.; Strauser, David; Chiu, Chung-Yi

2015-01-01

Multiple sclerosis (MS) is an unpredictable, sometimes progressive chronic illness affecting people in the prime of their working lives. This article reviews the effects of MS on employment based on the World Health Organization's International Classification of Functioning, Disability and Health model. Correlations between employment and…

Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis.

PubMed

Tiedje, V; Schlamann, M; Führer, D; Moeller, L C

2013-10-01

Multiple sclerosis (MS) is a complex neurodegenerative disease presenting with a diversity of clinical symptoms including palsy and cognitive impairment. We present a 59-year-old woman with a history of secondary progressive MS since 1987, who was referred to our department because of recent onset of confusion and polydipsia. Initial lab tests showed mildly elevated serum sodium levels and low urine osmolality. Under water deprivation, diuresis and low urine osmolality persisted and serum sodium levels rose above 150 mmol/l. Oral desmopressin resulted in normalisation of serum sodium as well as urine osmolarity, confirming a diagnosis of central diabetes insipidus. As drug-induced diabetes could be excluded, pituitary magnetic resonance imaging (MRI) was performed. A demyelinating lesion was detected in the hypothalamus. The patient was started on oral desmopressin treatment (0.2 mg/day). Fluid intake and serum sodium levels have since remained normal. In summary, we report the rare case of a patient presenting with diabetes insipidus due to progressive MS. Diabetes insipidus should be considered in MS patients who develop new onset of polydipsia.

Internally generated preactivation of single neurons in human medial frontal cortex predicts volition

PubMed Central

Fried, Itzhak; Mukamel, Roy; Kreiman, Gabriel

2011-01-01

Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over ~1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects’ awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold. PMID:21315264

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

PubMed

Freedman, Mark S; Selchen, Daniel; Arnold, Douglas L; Prat, Alexandre; Banwell, Brenda; Yeung, Michael; Morgenthau, David; Lapierre, Yves

2013-05-01

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Finger and foot tapping as alternative outcomes of upper and lower extremity function in multiple sclerosis.

PubMed

Tanigawa, Makoto; Stein, Jason; Park, John; Kosa, Peter; Cortese, Irene; Bielekova, Bibiana

2017-01-01

While magnetic resonance imaging contrast-enhancing lesions represent an excellent screening tool for disease-modifying treatments in relapsing-remitting multiple sclerosis (RRMS), this biomarker is insensitive for testing therapies against compartmentalized inflammation in progressive multiple sclerosis (MS). Therefore, alternative sensitive outcomes are needed. Using machine learning, clinician-acquired disability scales can be combined with timed measures of neurological functions such as walking speed (e.g. 25-foot walk; 25FW) or fine finger movements (e.g. 9-hole peg test; 9HPT) into sensitive composite clinical scales, such as the recently developed combinatorial, weight-adjusted disability scale (CombiWISE). Ideally, these complementary simplified measurements of certain neurological functions could be performed regularly at patients' homes using smartphones. We asked whether tests amenable to adaptation to smartphone technology, such as finger and foot tapping have comparable sensitivity and specificity to current non-clinician-acquired disability measures. We observed that finger and foot tapping can differentiate RRMS and progressive MS in a cross-sectional study and can also measure yearly and two-year disease progression in the latter, with better power (based on z-scores) in comparison to currently utilized 9HPT and 25FW. Replacing the 9HPT and 25FW with simplified tests broadly adaptable to smartphone technology may enhance the power of composite scales for progressive MS.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Natural history of multiple sclerosis from the Indian perspective: Experience from a tertiary care hospital.

PubMed

Jena, Subhransu S; Alexander, Mathew; Aaron, Sanjith; Mathew, Vivek; Thomas, Maya Mary; Patil, Anil K; Sivadasan, Ajith; Muthusamy, Karthik; Mani, Sunithi; Rebekah, J Grace

2015-01-01

Multiple sclerosis (MS) has a spectrum of heterogeneity, as seen in western and eastern hemispheres, in the clinical features, topography of involvement and differences in natural history. To study the clinical spectrum, imaging, and electrophysiological as well as cerebrospinal fluid (CSF) characteristics and correlate them with outcome. Retrospective analysis of MS patients during a period of 20 years. Cases were selected according to recent McDonald's criteria (2010), They were managed in the Department of Neurology, Christian Medical College, Vellore. Chi-square and Fisher's exact tests were used for categorical variables. Multiple binary logistic regressions were done to assess significance. Kaplan-Meier curves were drawn to estimate the time to irreversible disability. A total of 157 patients with female preponderance (55%) were included. The inter quartile range duration of follow-up was 9.1 (8.2, 11) years for 114 patients, who were included for final outcome analysis. Relapsing remitting MS (RRMS) (54.1%) was the most common type of MS seen. RRMS had a significantly better outcome (odds ratio: 0.12, 95% confidence interval: 0.02-0.57, P = 0.008) compared to progressive form of MS (primary progressive, secondary progressive). The Expanded Disability Status Scale score of patients at presentation and at final follow-up was 4.4 ± 1.31 and 4.1 ± 2.31, respectively. During the first presentation, polysymptomatic manifestations like motor and sphincteric involvement, incomplete recovery from the first attack; and, during the disease course, bowel, bladder, cerebellar and pyramidal affliction, predicted a worse outcome. A high incidence of optico-spinal presentation, predominance of RRMS and a low yield on cerebrospinal fluid (CSF) studies are the major findings of our study. A notable feature was the analysis of prognostic markers of disability.

Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

PubMed

Garcia-Martin, Elena; Ara, Jose R; Martin, Jesus; Almarcegui, Carmen; Dolz, Isabel; Vilades, Elisa; Gil-Arribas, Laura; Fernandez, Francisco J; Polo, Vicente; Larrosa, Jose M; Pablo, Luis E; Satue, Maria

2017-05-01

To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. Observational and longitudinal study. One hundred patients with relapsing-remitting MS and 50 healthy controls. All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Association study of two functional single nucleotide polymorphisms of neuropeptide y gene with multiple sclerosis.

PubMed

Mohammadi, Seyed Mahdi; Shirvani Farsani, Zeinab; Dosti, Rozita; Sahraian, Mohammad Ali; Behmanesh, Mehrdad

2016-12-01

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by brain inflammation, demyelination and axonal loss. Neuropeptide Y (NPY) has a critical role in the maintenance of homeostasis in the immune system and coping of stress condition. In the current study we analyzed 188 patients suffering from MS and 204 unrelated healthy controls for two functional single nucleotide polymorphisms (SNPs), NPY 20T>C (rs16139) and NPY -485T>C (rs16147) using PCR-RFLP and Mismatch PCR-RFLP methods. Our results demonstrated that homozygocity in the minor allele for NPY -485T>C polymorphism is associated with the MS risk in patients in compare with healthy controls (CC vs. TT, P=0.033; CC vs. TT+TC, P=0.02). In addition, by comparison with allele T, the frequency of NPY -485C allele was higher in cases than in control subjects and present increased risk of MS, but statistically significant was borderline (P=0.053). The stratification for disease progression revealed a significant difference in the allelic and genotypic distribution between subgroups of MS and controls. The frequency of the CC genotype and C allele was higher in the primary progressive MS patients when compared with control group (CC vs. TT, P=0.019; CC vs. TT+TC, P=0.008; C vs. T, P=0.022). In addition, the frequency of CC genotype was higher in the relapsing remitting MS patients when compared with control group (CC vs. TT, P=0.034; CC vs. TT+TC, P=0.016). Haplotype analysis demonstrated that the haplotype 3 (CT) is more common in RR MS (P=0.041), and PP MS (P=0.031) than control group. In conclusion, the obtained results demonstrate the probable role of NPY SNPs in susceptibility to MS within the Iranian population. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mass spectrometric identification of proteins in complex post-genomic projects. Soluble proteins of the metabolically versatile, denitrifying 'Aromatoleum' sp. strain EbN1.

PubMed

Hufnagel, Peter; Rabus, Ralf

2006-01-01

The rapidly developing proteomics technologies help to advance the global understanding of physiological and cellular processes. The lifestyle of a study organism determines the type and complexity of a given proteomic project. The complexity of this study is characterized by a broad collection of pathway-specific subproteomes, reflecting the metabolic versatility as well as the regulatory potential of the aromatic-degrading, denitrifying bacterium 'Aromatoleum' sp. strain EbN1. Differences in protein profiles were determined using a gel-based approach. Protein identification was based on a progressive application of MALDI-TOF-MS, MALDI-TOF-MS/MS and LC-ESI-MS/MS. This progression was result-driven and automated by software control. The identification rate was increased by the assembly of a project-specific list of background signals that was used for internal calibration of the MS spectra, and by the combination of two search engines using a dedicated MetaScoring algorithm. In total, intelligent bioinformatics could increase the identification yield from 53 to 70% of the analyzed 5,050 gel spots; a total of 556 different proteins were identified. MS identification was highly reproducible: most proteins were identified more than twice from parallel 2DE gels with an average sequence coverage of >50% and rather restrictive score thresholds (Mascot >or=95, ProFound >or=2.2, MetaScore >or=97). The MS technologies and bioinformatics tools that were implemented and integrated to handle this complex proteomic project are presented. In addition, we describe the basic principles and current developments of the applied technologies and provide an overview over the current state of microbial proteome research. Copyright (c) 2006 S. Karger AG, Basel.

Cueing listeners to attend to a target talker progressively improves word report as the duration of the cue-target interval lengthens to 2,000 ms.

PubMed

Holmes, Emma; Kitterick, Padraig T; Summerfield, A Quentin

2018-04-25

Endogenous attention is typically studied by presenting instructive cues in advance of a target stimulus array. For endogenous visual attention, task performance improves as the duration of the cue-target interval increases up to 800 ms. Less is known about how endogenous auditory attention unfolds over time or the mechanisms by which an instructive cue presented in advance of an auditory array improves performance. The current experiment used five cue-target intervals (0, 250, 500, 1,000, and 2,000 ms) to compare four hypotheses for how preparatory attention develops over time in a multi-talker listening task. Young adults were cued to attend to a target talker who spoke in a mixture of three talkers. Visual cues indicated the target talker's spatial location or their gender. Participants directed attention to location and gender simultaneously ("objects") at all cue-target intervals. Participants were consistently faster and more accurate at reporting words spoken by the target talker when the cue-target interval was 2,000 ms than 0 ms. In addition, the latency of correct responses progressively shortened as the duration of the cue-target interval increased from 0 to 2,000 ms. These findings suggest that the mechanisms involved in preparatory auditory attention develop gradually over time, taking at least 2,000 ms to reach optimal configuration, yet providing cumulative improvements in speech intelligibility as the duration of the cue-target interval increases from 0 to 2,000 ms. These results demonstrate an improvement in performance for cue-target intervals longer than those that have been reported previously in the visual or auditory modalities.

Quality of life and social support in patients with multiple sclerosis.

PubMed

Rosiak, Katarzyna; Zagożdżon, Paweł

2017-10-29

Quality of life and needforsocial support in persons diagnosed with multiple sclerosis (MS) are to a large extent determined by the degree of their disability. The aim of the study was to analyze an association between specific forms of MS, subjectively perceived quality of life and social support. The study included subjects with established diagnosis of MS, treated at rehabilitation centers, hospitals and in a home setting, as well as the members of patient organizations. After being informed about objectives of the study, type of included tasks and way to complete them, each participant was handed out a set of questionnaires: Berlin Social Support Scales (Łuszczyńska, Kowalska, Schwarzer, Schulz), Quality of Life Questionnaire (WHOQOLBREF), as well as a survey developed specifically for the purposes of this project. The results were subjected to statistical analysis with STATA 12 package. The study included a total of 110 persons (67 women and 43 men). Quality of life overall, as well in physical, psychological, social relationships and environmental health domains, turned out to be particularly important in patients with primary-progressive MS. Irrespective of MS type, social support overall did not play a significant role on univariate analysis. However, subgroup analysis according to sex demonstrated that men with MS received social support four times less often than women. Quality of life in individuals with primary-progressive MS is significantly lower than in patients presenting with other types of this disease. Men with MS are more likely to present with worse scores for social support overall. They are less likely both to acknowledge the need for support and to realize the availability of support they actually need.

Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis.

PubMed

Sternberg, Zohara; Sternberg, Daniel; Drake, Allison; Chichelli, Trevor; Yu, Jinhee; Hojnacki, David

2014-09-15

This study is one in a series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) and its potential as a biomarker in multiple sclerosis (MS). We evaluated serum levels of the endogenous secretory RAGE (esRAGE) in MS patients and assessed the relationship between esRAGE levels and the use of disease modifying drugs (DMDs), and between esRAGE levels and indicators of MS disease severity. esRAGE serum levels were compared between 98 MS patients and 34 healthy controls (HCs) using ELISA. esRAGE serum levels were similar between MS and HCs. DMD-treated patients had higher esRAGE serum levels than DMD-naïve patients (395.7±38.6pg/ml vs. 299.2±20.1pg/ml, P=0.02). DMD-naïve, primary progressive (PP) patients had higher esRAGE serum levels, than relapsing remitting (RR) (P=0.02) and secondary progressive (SP) (P=0.04) patients; RRMS patients in clinical relapse had lower esRAGE serum levels than clinically stable patients (219.7±30.0pg/ml vs. 338.2±31.6pg/ml, P=0.02). In a univariate regression analysis of DMD-naïve MS patients, esRAGE serum levels inversely correlated with the rate of clinical relapse (r=-0.44, P=0.006), MS severity scale (MSSS) (r=-0.32, P=0.03), and expanded disability status scale (EDSS) (r=-0.251, P=0.07). esRAGE serum levels are modulated by DMDs. The serum levels may be a useful biomarker of MS clinical relapse. Published by Elsevier B.V.

Excess Mortality in Patients with Multiple Sclerosis Starts at 20 Years from Clinical Onset: Data from a Large-Scale French Observational Study

PubMed Central

Leray, Emmanuelle; Vukusic, Sandra; Debouverie, Marc; Clanet, Michel; Brochet, Bruno; de Sèze, Jérôme; Zéphir, Hélène; Defer, Gilles; Lebrun-Frenay, Christine; Moreau, Thibault; Clavelou, Pierre; Pelletier, Jean; Berger, Eric; Cabre, Philippe; Camdessanché, Jean-Philippe; Kalson-Ray, Shoshannah; Confavreux, Christian; Edan, Gilles

2015-01-01

Background Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France. Objectives Estimate survival in MS patients and compare mortality with that of the French general population. Methods We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration. Results After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients (F/M sex ratio 2.5, mean age at onset 33.0 years, 85.5% relapsing onset). During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate (Standardized Mortality Ratio 1.48, 95% confidence interval [1.41-1.55]), but increased considerably after 20 years of disease (2.20 [2.10-2.31]). Conclusions This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression. PMID:26148099

Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis.

PubMed

Miller, Deborah M; Bethoux, Francois; Victorson, David; Nowinski, Cindy J; Buono, Sarah; Lai, Jin-Shei; Wortman, Katy; Burns, James L; Moy, Claudia; Cella, David

2016-05-01

Multiple sclerosis (MS) is a chronic, progressive, and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease-specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. The objective of this research paper is to conduct an initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS patients. Internal consistency was high for all measures (α = 0.81-0.95) and ICCs were within the acceptable range (0.76-0.91); concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. The Neuro-QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and known groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS. © The Author(s), 2015.

The regulator's perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future?

PubMed

Crommelin, Daan Ja; Broich, Karl; Holloway, Chris; Meesen, Bianca; Lizrova Preiningerova, Jana; Prugnaud, Jean-Louis; Silva-Lima, Beatriz

2016-08-01

Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for improving patient disease management. New therapies are also under development and pose challenges to the regulatory bodies regarding the optimal design of clinical trials with more patient-focused clinical endpoints. Moreover, with the upcoming patent expiry of some of the key first-line MS treatments in Europe, regulatory bodies will also face the challenge of recommending marketing authorisation for generic and abridged versions based on appropriate requirements for demonstrating equality/similarity to the innovator's product. The goal of this article is to improve the understanding of the relevant guidance documents of the European Medicines Agency (EMA) on clinical investigation of medicinal products and to highlight the issues that the agency will need to clarify regarding follow-on products of first-line MS treatments. Today, it is clear that close collaboration between patients, healthcare professionals, regulatory bodies and industry is crucial for developing new safe and effective drugs, which satisfy the needs of MS patients. © The Author(s), 2016.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

PubMed

Broadley, Simon A; Barnett, Michael H; Boggild, Mike; Brew, Bruce J; Butzkueven, Helmut; Heard, Robert; Hodgkinson, Suzanne; Kermode, Allan G; Lechner-Scott, Jeannette; Macdonell, Richard A L; Marriott, Mark; Mason, Deborah F; Parratt, John; Reddel, Stephen W; Shaw, Cameron P; Slee, Mark; Spies, Judith; Taylor, Bruce V; Carroll, William M; Kilpatrick, Trevor J; King, John; McCombe, Pamela A; Pollard, John D; Willoughby, Ernest

2014-11-01

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Newly diagnosed multiple sclerosis in state of Qatar.

PubMed

Akhtar, N; Elsetouhy, A; Deleu, D; Kamran, S; AlHail, H; Elalamy, O; Mesraoua, B; Sokrab, T; Kamil, H; Melikyan, G; D'souza, A; Osman, Y; Imam, Y

2013-08-01

Epidemiologic studies on multiple sclerosis (MS) are well-documented in the western population but to a lesser extent in Arab world. To study the demographics, clinical aspects, radiologic and laboratory features along with the degree of disability inflicted, and factors affecting disease progression and outcome of newly diagnosed MS patients at our institution. Data from all newly diagnosed MS patients fulfilling McDonald criteria from January 01, 2005 to December 31, 2010 were collected and analyzed. A total of 142 patients were identified, in which 82 (58%) were Qataris, and 90 (64%) females. Mean age was 31 years, and mean duration of symptoms was 24 days (median 15 days). Most common symptoms were sensory (63%), followed by visual (45%) and motor (43%). Mean EDSS was 2.3 at presentation. Treatment was given to 127 (89%), and relapse observed in 49%. Gadolinium enhancing lesions on follow-up MRI brain and relapsing remitting MS were associated with increased radiologic disease burden, while weakness at onset, EDSS of ≥2.5 and ≥3 clinical relapse was associated with clinical disease progression. MS in Qatar is an emerging disorder especially in the native population. The pattern of disease differs from other Middle Eastern countries by its milder clinical and aggressive radiologic disease presentation. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of optic neuritis on progressive axonal damage in multiple sclerosis patients.

PubMed

Garcia-Martin, E; Pueyo, V; Ara, J R; Almarcegui, C; Martin, J; Pablo, L; Dolz, I; Sancho, E; Fernandez, F J

2011-07-01

The objective of this research was to study the effect of optic neuritis (ON) on axonal damage in multiple sclerosis (MS) patients. Specifically, we compared changes over 2 years in the retinal nerve fibre layer (RNFL) between affected and contralateral eyes in MS patients with a prior history of ON. Thirty-four patients with one unilateral definitive episode of ON were included and underwent a complete ophthalmic examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials (VEP) and pattern electroretinogram (pERG). All patients were re-evaluated at 12 and 24 months. Parameters were compared between ON-affected and contralateral eyes in an initial exploration and over the course of the follow-up. Correlations between parameter changes were analysed. RNFL thickness and functional parameters showed more affection in ON eyes (p ≤ 0.05), but changes in measurements during the study were similar between both groups of eyes. Progressive axonal loss can be detected in the optic nerve, but ON is not a risk factor for increased chronic damage in MS patients without ophthalmic relapses. Loss of the RNFL is caused by progressive degeneration associated with the disease.

Machine Learning Approach for Classifying Multiple Sclerosis Courses by Combining Clinical Data with Lesion Loads and Magnetic Resonance Metabolic Features.

PubMed

Ion-Mărgineanu, Adrian; Kocevar, Gabriel; Stamile, Claudio; Sima, Diana M; Durand-Dubief, Françoise; Van Huffel, Sabine; Sappey-Marinier, Dominique

2017-01-01

Purpose: The purpose of this study is classifying multiple sclerosis (MS) patients in the four clinical forms as defined by the McDonald criteria using machine learning algorithms trained on clinical data combined with lesion loads and magnetic resonance metabolic features. Materials and Methods: Eighty-seven MS patients [12 Clinically Isolated Syndrome (CIS), 30 Relapse Remitting (RR), 17 Primary Progressive (PP), and 28 Secondary Progressive (SP)] and 18 healthy controls were included in this study. Longitudinal data available for each MS patient included clinical (e.g., age, disease duration, Expanded Disability Status Scale), conventional magnetic resonance imaging and spectroscopic imaging. We extract N -acetyl-aspartate (NAA), Choline (Cho), and Creatine (Cre) concentrations, and we compute three features for each spectroscopic grid by averaging metabolite ratios (NAA/Cho, NAA/Cre, Cho/Cre) over good quality voxels. We built linear mixed-effects models to test for statistically significant differences between MS forms. We test nine binary classification tasks on clinical data, lesion loads, and metabolic features, using a leave-one-patient-out cross-validation method based on 100 random patient-based bootstrap selections. We compute F1-scores and BAR values after tuning Linear Discriminant Analysis (LDA), Support Vector Machines with gaussian kernel (SVM-rbf), and Random Forests. Results: Statistically significant differences were found between the disease starting points of each MS form using four different response variables: Lesion Load, NAA/Cre, NAA/Cho, and Cho/Cre ratios. Training SVM-rbf on clinical and lesion loads yields F1-scores of 71-72% for CIS vs. RR and CIS vs. RR+SP, respectively. For RR vs. PP we obtained good classification results (maximum F1-score of 85%) after training LDA on clinical and metabolic features, while for RR vs. SP we obtained slightly higher classification results (maximum F1-score of 87%) after training LDA and SVM-rbf on clinical, lesion loads and metabolic features. Conclusions: Our results suggest that metabolic features are better at differentiating between relapsing-remitting and primary progressive forms, while lesion loads are better at differentiating between relapsing-remitting and secondary progressive forms. Therefore, combining clinical data with magnetic resonance lesion loads and metabolic features can improve the discrimination between relapsing-remitting and progressive forms.

Complementary and alternative medicine for the treatment of multiple sclerosis

PubMed Central

Yadav, Vijayshree; Shinto, Lynne; Bourdette, Dennis

2010-01-01

Multiple sclerosis (MS) is a chronic disabling disease of the CNS that affects people during early adulthood. Despite several US FDA-approved medications, the treatment options in MS are limited. Many people with MS explore complementary and alternative medicine (CAM) treatments to help control their MS and treat their symptoms. Surveys suggest that up to 70% of people with MS have tried one or more CAM treatment for their MS. People with MS using CAM generally report deriving some benefit from the therapies. The CAM therapies most frequently used include diet, omega-3 fatty acids and antioxidants. There is very limited research evaluating the safety and effectiveness of CAM in MS. The most promising among CAM therapies that warrant further investigation are a low-fat diet, omega-3 fatty acids, lipoic acid and vitamin D supplementation as potential anti-inflammatory and neuroprotective agents in both relapsing and progressive forms of MS. There is very limited research evaluating the safety and effectiveness of CAM in MS. However, in recent years, the NIH and the National MS Society have been actively supporting the research in this very important area. PMID:20441425

Visual Evoked Potential and Magnetic Resonance Imaging are More Effective Markers of Multiple Sclerosis Progression than Laser Polarimetry with Variable Corneal Compensation.

PubMed

Kantorová, Ema; Ziak, Peter; Kurča, Egon; Koyšová, Mária; Hladká, Mária; Zeleňák, Kamil; Michalik, Jozef

2014-01-01

The aim of our study was to assess the role of laser polarimetry and visual evoked potentials (VEP) as potential biomarkers of disease progression in multiple sclerosis (MS). A total of 41 patients with MS (82 eyes) and 22 age-related healthy volunteers (44 eyes) completed the study. MS patients were divided into two groups, one (ON) with a history of optic neuritis (17 patients, 34 eyes) and another group (NON) without it (24 patients, 48 eyes). The MS patients and controls underwent laser polarimetry (GDx) examination of the retinal nerve fiber layer (RNFL). In the MS group, we also examined: Kurtzke "expanded disability status scale" (EDSS), the duration of the disorder, VEP - latency and amplitude, and conventional brain magnetic resonance imaging (MRI). Our results were statistically analyzed using ANOVA, Mann-Whitney, and Spearman correlation analyses. In the MS group, brain atrophy and new T2 brain lesions in MRI correlated with both VEP latencies and amplitudes. Separate comparisons revealed VEP latency testing to be less sensitive in ON than in NON-patients. In ON patients, VEP amplitudes correlated mildly with brain atrophy (r = -0.15) and strongly with brain new MRI lesions (r = -0.8). In NON-patients, highly significant correlation of new MRI brain lesions with VEP latencies (r = 0.63, r = 0.6) and amplitudes (r = -0.3, r = -4.2) was found. EDSS also correlated with brain atrophy in this group (r = 0.5). Our study did not find a correlation of GDx measures with MRI tests. The GDx method was not able to detect whole brain demyelinization and the degeneration process, but was only able to reveal the involvement of optic nerves in ON and NON-patients. In our study, we found that both methods (VEP and GDx) can be used for the detection of optic nerve damage, but VEP was found to be superior in evaluating whole brain demyelinization and axonal degeneration. Both VEP and MRI, but not GDx, have an important role in monitoring disease progression in MS patients, independent of the ON history.

Novel therapeutics in multiple sclerosis management: clinical applications.

PubMed

Leist, Thomas; Hunter, Samuel F; Kantor, Daniel; Markowitz, Clyde

2014-01-01

Multiple sclerosis (MS) affects an estimated 300,000 individuals in the United States. No cure exists and although there is a lack of consensus on management, strategies to modify disease course are available. These strategies involve initiating disease-modifying therapies that have been found to slow disease progression and prevent disability symptoms, thereby improving function for MS patients. The overall goal of early disease management is to intervene prior to irreversible neuronal destruction in order to delay disability progression and improve quality of life. Maintaining a lower level of disability for a longer period of time postpones and ultimately attempts to prevent reaching a level of immobility and irreversible disability. However, due to the complex nature of disease and its unique, individual patient course, no patient can be treated alike and no patient responds to therapy similarly. Therefore, MS research is continuous in its evolution of therapeutic development, focusing on neuroprotective effects and agents with distinctive mechanisms of action allowing for unique safety and efficacy profiles. Investigations include novel oral agents and monoclonal antibodies. Many of the approved agents also are continually being investigated in order to evaluate comparative data, the most appropriate means of implementing subsequent therapy upon failure, responsiveness to therapeutic agent when switched, and long-term safety and efficacy. This multimedia webcast educational activity will cover the current state of MS science, current therapies in MS, emerging treatments in clinical trials for MS as well as differences between physicians in diagnosis and management of MS and their evolving practices. Copyright © 2014. Published by Elsevier Inc.

Chaos theory for clinical manifestations in multiple sclerosis.

PubMed

Akaishi, Tetsuya; Takahashi, Toshiyuki; Nakashima, Ichiro

2018-06-01

Multiple sclerosis (MS) is a demyelinating disease which characteristically shows repeated relapses and remissions irregularly in the central nervous system. At present, the pathological mechanism of MS is unknown and we do not have any theories or mathematical models to explain its disseminated patterns in time and space. In this paper, we present a new theoretical model from a viewpoint of complex system with chaos model to reproduce and explain the non-linear clinical and pathological manifestations in MS. First, we adopted a discrete logistic equation with non-linear dynamics to prepare a scalar quantity for the strength of pathogenic factor at a specific location of the central nervous system at a specific time to reflect the negative feedback in immunity. Then, we set distinct minimum thresholds in the above-mentioned scalar quantity for demyelination possibly causing clinical relapses and for cerebral atrophy. With this simple model, we could theoretically reproduce all the subtypes of relapsing-remitting MS, primary progressive MS, and secondary progressive MS. With the sensitivity to initial conditions and sensitivity to minute change in parameters of the chaos theory, we could also reproduce the spatial dissemination. Such chaotic behavior could be reproduced with other similar upward-convex functions with appropriate set of initial conditions and parameters. In conclusion, by applying chaos theory to the three-dimensional scalar field of the central nervous system, we can reproduce the non-linear outcome of the clinical course and explain the unsolved disseminations in time and space of the MS patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

The emerging role of native mass spectrometry in characterizing the structure and dynamics of macromolecular complexes

PubMed Central

Boeri Erba, Elisabetta; Petosa, Carlo

2015-01-01

Mass spectrometry (MS) is a powerful tool for determining the mass of biomolecules with high accuracy and sensitivity. MS performed under so-called “native conditions” (native MS) can be used to determine the mass of biomolecules that associate noncovalently. Here we review the application of native MS to the study of protein−ligand interactions and its emerging role in elucidating the structure of macromolecular assemblies, including soluble and membrane protein complexes. Moreover, we discuss strategies aimed at determining the stoichiometry and topology of subunits by inducing partial dissociation of the holo-complex. We also survey recent developments in "native top-down MS", an approach based on Fourier Transform MS, whereby covalent bonds are broken without disrupting non-covalent interactions. Given recent progress, native MS is anticipated to play an increasingly important role for researchers interested in the structure of macromolecular complexes. PMID:25676284

CE-TOF/MS: fundamental concepts, instrumental considerations and applications.

PubMed

Staub, Aline; Schappler, Julie; Rudaz, Serge; Veuthey, Jean-Luc

2009-05-01

This review discusses the fundamental principles of TOF analyzers and covers the great progress that has been made in this area in recent years (i.e. orthogonal acceleration, reflectron). This paper also gives an overview of applications performed by CE coupled to TOF/MS detection. The main domains of interest include the analysis of biomolecules and natural compounds.

New Approaches to the Diagnosis, Clinical Course, and Goals of Therapy in Multiple Sclerosis and Related Disorders.

PubMed

Krieger, Stephen C

2016-06-01

The diagnosis, categorization, and treatment of multiple sclerosis (MS) and other demyelinating diseases have shifted over the past decade, and many of the fundamental principles of MS pathogenesis and clinical course are being rewritten. Fundamental issues include selecting the right disease-modifying therapy for someone with active disease and how, or even if, patients with purely progressive MS should be treated. This article provides an overview and introduction to the current thinking in MS diagnosis and therapy with an emphasis on the data-driven and proactive approach that has come to define the current state of the art.

The Spatial Power Motivation Scale: a semi-implicit measure of situational power motivation.

PubMed

Schoel, Christiane; Zimmer, Katharina; Stahlberg, Dagmar

2015-01-01

We introduce a new nonverbal and unobtrusive measure to assess power motive activation, the Spatial Power Motivation Scale (SPMS). The unique features of this instrument are that it is (a) very simple and economical, (b) reliable and valid, and (c) sensitive to situational changes. Study 1 demonstrates the instrument's convergent and discriminant validity with explicit measures. Study 2 demonstrates the instrument's responsiveness to situational power motive salience: anticipating and winning competition versus losing competition and watching television. Studies 3 and 4 demonstrate that thoughts of competition result in higher power motivation specifically for individuals with a high dispositional power motive.

Care Partners and Multiple Sclerosis

PubMed Central

Quig, Mary Elizabeth; Tyry, Tuula; Marrie, Ruth Ann; Cutter, Gary; Shearin, Edward; Johnson, Kamau; Simsarian, James

2015-01-01

Background: Caring for someone with multiple sclerosis (MS) can be a stressful experience that requires clinical attention. We investigated the impact of caregiver stress on the emotional well-being and physical health of the MS care partner using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. Methods: Care partners of NARCOMS participants were invited to complete an online questionnaire that captured demographic characteristics, health status, caregiver burden as measured by the Zarit Caregiver Burden Interview, and impact of caregiving on employment. Results: Of 1446 care partners who agreed to participate, 1333 had complete data. Most were men (n = 825, 61.9%), with a mean (SD) age of 51.1 (11.2) years. The mean (SD) Zarit total score was 24.6 (15.1), placing the overall group in the mild caregiver burden range. Compared with male care partners, female care partners reported higher levels of burden and stress and more medication use for stress/anxiety and mood disorders. Male care partners were more likely to report physical concerns. Care partners of people with primary progressive MS reported greater perceived burden than did partners of people with secondary progressive MS and relapsing-remitting MS. More than 40% of care partners (559 of 1288) had missed work during the past year owing to caregiving responsibilities. Conclusions: Care partners of people with MS have substantial physical and psychological health concerns and experience an adverse impact on employment. Future research should evaluate how to mitigate the adverse effects of caregiving and evaluate positive aspects of the role. PMID:26664330

Prismatic displacement effect of progressive multifocal glasses on reaction time and accuracy in elderly people.

PubMed

Ellison, Ashton C; Campbell, A John; Robertson, M Clare; Sanderson, Gordon F

2014-01-01

Multifocal glasses (bifocals, trifocals, and progressives) increase the risk of falling in elderly people, but how they do so is unclear. To explain why glasses with progressive addition lenses increase the risk of falls and whether this can be attributed to false projection, this study aimed to 1) map the prismatic displacement of a progressive lens, and 2) test whether this displacement impaired reaction time and accuracy. The reaction times of healthy ≥75-year-olds (31 participants) were measured when grasping for a bar and touching a black line. Participants performed each test twice, wearing their progressives and new, matched single vision (distance) glasses in random order. The line and bar targets were positioned according to the maximum and minimum prismatic displacement effect through the progressive lens, mapped using a focimeter. Progressive spectacle lenses have large areas of prismatic displacement in the central visual axis and edges. Reaction time was faster for progressives compared with single vision glasses with a centrally-placed horizontal grab bar (mean difference 101 ms, P=0.011 [repeated measures analysis]) and a horizontal black line placed 300 mm below center (mean difference 80 ms, P=0.007). There was no difference in accuracy between the two types of glasses. Older people appear to adapt to the false projection of progressives in the central visual axis. This adaptation means that swapping to new glasses or a large change in prescription may lead to a fall. Frequently updating glasses may be more beneficial.

The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis.

PubMed

Dolei, Antonina

2018-01-01

Two human endogenous retroviruses of the HERV-W family are proposed as multiple sclerosis (MS) co-factors: MS-associated retrovirus (MSRV) and ERVWE1, whose env proteins showed several potentially neuropathogenic features, in vitro and in animal models. Phase II clinical trials against HERV-Wenv are ongoing. HERV-W/MSRV was repeatedly found in MS patients, in striking parallel with MS stages, active/remission phases, and therapy outcome. The HERV-Wenv protein is highly expressed in active MS plaques. Early MSRV presence in spinal fluids predicted worst MS progression 10 years in advance. Effective anti-MS therapies strongly reduced MSRV/Syncytin-1/HERV-W expression. The Epstein-Barr virus (EBV) activates HERV-W/MSRV in vitro and in vivo, in patients with infectious mononucleosis and controls with high anti-EBNA1-IgG titers. Thus, the two main EBV/MS links (infectious mononucleosis and high anti-EBNA1-IgG titers) are paralleled by activation of HERV-W/MSRV. It is hypothesized that EBV may act as initial trigger of future MS, years later, by activating MSRV, which would act as direct neuropathogenic effector, before and during MS.

Orthodontic treatment for a patient with multiple sclerosis

PubMed Central

Bakathir, Manal A

2017-01-01

Multiple sclerosis (MS) is a chronic, autoimmune inflammatory disorder of the central nervous system (CNS) that affects myelinated axons, destroying the myelin and damaging axons to varying degrees. The course of MS is highly varied and unpredictable. Metals used during orthodontic treatment can negatively affect imaging techniques used to diagnose and monitor the progression of MS, while medications used to treat MS can negatively affect orthodontic tooth movement. The present case report highlights some of the challenges encountered during orthodontic treatment of a patient with MS and how to overcome them. The patient was a 20-year-old woman with complaints of diastema and spacing in the upper arch. Although closing the spaces was challenging due to some of the MS medications, she was treated successfully, without complications, within 20 months using closing loops. PMID:28717636

Women in PR: Progression or Retrogression?

ERIC Educational Resources Information Center

Mathews, Wilma

1988-01-01

Contends that the issue that most determines women's progress in leadership and management is pay equity. Concludes that women need to overcome their temerity in dealing openly with financial matters and combine their resources, talents, and energies before they can hope to overcome unequal pay treatment and attain equality. (MS)

Estimating Time to Event From Longitudinal Categorical Data: An Analysis of Multiple Sclerosis Progression.

PubMed

Mandel, Micha; Gauthier, Susan A; Guttmann, Charles R G; Weiner, Howard L; Betensky, Rebecca A

2007-12-01

The expanded disability status scale (EDSS) is an ordinal score that measures progression in multiple sclerosis (MS). Progression is defined as reaching EDSS of a certain level (absolute progression) or increasing of one point of EDSS (relative progression). Survival methods for time to progression are not adequate for such data since they do not exploit the EDSS level at the end of follow-up. Instead, we suggest a Markov transitional model applicable for repeated categorical or ordinal data. This approach enables derivation of covariate-specific survival curves, obtained after estimation of the regression coefficients and manipulations of the resulting transition matrix. Large sample theory and resampling methods are employed to derive pointwise confidence intervals, which perform well in simulation. Methods for generating survival curves for time to EDSS of a certain level, time to increase of EDSS of at least one point, and time to two consecutive visits with EDSS greater than three are described explicitly. The regression models described are easily implemented using standard software packages. Survival curves are obtained from the regression results using packages that support simple matrix calculation. We present and demonstrate our method on data collected at the Partners MS center in Boston, MA. We apply our approach to progression defined by time to two consecutive visits with EDSS greater than three, and calculate crude (without covariates) and covariate-specific curves.

Stress and the Student with Autism Spectrum Disorders: Strategies for Stress Reduction and Enhanced Learning

ERIC Educational Resources Information Center

Lytle, Rebecca; Todd, Teri

2009-01-01

Shane, who is in Ms. Jones's third-grade class, has autism. Ms. Jones has provided him with a schedule, a picture communication system, and a positive reinforcement system for his learning tasks. He is demonstrating progress toward his individualized education program (IEP) goals, but he still struggles with attending for any length of time,…

In Vivo Imaging of Cortical Inflammation and Subpial Pathology in Multiple Sclerosis by Combined PET and MRI

DTIC Science & Technology

2014-09-01

and Subpial Pathology in Multiple Sclerosis by Combined PET and MRI PRINCIPAL INVESTIGATOR: Dr. Caterina Mainero...studies in multiple sclerosis (MS) suggested that cortical demyelinating lesions, which are hardly detected in vivo on conventional magnetic resonance...disease progression in many MS cases. 15. SUBJECT TERMS Multiple sclerosis ; cortex; cortical sulci; neuroinflammation; microglia; cortical

Estimate of the cost of multiple sclerosis in Spain by literature review.

PubMed

Fernández, Oscar; Calleja-Hernández, Miguel Angel; Meca-Lallana, José; Oreja-Guevara, Celia; Polanco, Ana; Pérez-Alcántara, Ferran

2017-08-01

Multiple Sclerosis (MS) is a progressive disease leading to increasing disability and costs. A literature review was carried out to identify MS costs and to estimate its economic burden in Spain. Areas Covered: The public electronic databases PubMed, ScienceDirect and IBECS were consulted and a manual review of communications presented at related congresses was carried out. A total of 225 references were obtained, of which 43 were finally included in the study. Expert Commentary: Three major cost groups were identified: direct healthcare costs, direct non-healthcare costs and indirect costs. There is a direct relationship between disease progression and increased costs, mainly direct non-healthcare costs (greater need for informal care) and indirect costs (greater loss of productivity). The total cost associated with MS in Spain is €1,395 million per year, and that the mean annual cost per patient is €30,050. Beyond costs, a large impact on the quality of life of patients, with an annual loss of up to 13,000 quality-adjusted life years was also estimated. MS has a large economic impact on Spanish society and a significant impact on the quality of life of patients.

Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions

PubMed Central

Gillen, Kelly M.; Mubarak, Mayyan; Nguyen, Thanh D.; Pitt, David

2018-01-01

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression. PMID:29515576

Resting State Brain Entropy Alterations in Relapsing Remitting Multiple Sclerosis.

PubMed

Zhou, Fuqing; Zhuang, Ying; Gong, Honghan; Zhan, Jie; Grossman, Murray; Wang, Ze

2016-01-01

Brain entropy (BEN) mapping provides a novel approach to characterize brain temporal dynamics, a key feature of human brain. Using resting state functional magnetic resonance imaging (rsfMRI), reliable and spatially distributed BEN patterns have been identified in normal brain, suggesting a potential use in clinical populations since temporal brain dynamics and entropy may be altered in disease conditions. The purpose of this study was to characterize BEN in multiple sclerosis (MS), a neurodegenerative disease that affects millions of people. Since currently there is no cure for MS, developing treatment or medication that can slow down its progression represents a high research priority, for which validating a brain marker sensitive to disease and the related functional impairments is essential. Because MS can start long time before any measurable symptoms and structural deficits, assessing the dynamic brain activity and correspondingly BEN may provide a critical way to study MS and its progression. Because BEN is new to MS, we aimed to assess BEN alterations in the relapsing-remitting MS (RRMS) patients using a patient versus control design, to examine the correlation of BEN to clinical measurements, and to check the correlation of BEN to structural brain measures which have been more often used in MS studies. As compared to controls, RRMS patients showed increased BEN in motor areas, executive control area, spatial coordinating area, and memory system. Increased BEN was related to greater disease severity as measured by the expanded disability status scale (EDSS) and greater tissue damage as indicated by the mean diffusivity. Patients also showed decreased BEN in other places, which was associated with less disability or fatigue, indicating a disease-related BEN re-distribution. Our results suggest BEN as a novel and useful tool for characterizing RRMS.

Epidemiological study of multiple sclerosis in La Rioja.

PubMed

Bártulos Iglesias, M; Marzo Sola, M E; Estrella Ruiz, L A; Bravo Anguiano, Y

2015-01-01

Multiple sclerosis is a demyelinating disease that causes severe disability in younger patients. Many epidemiology studies have confirmed a variable prevalence. The objective of this study was to analyse the prevalence of this disease in La Rioja (Spain), using such variables as age and sex; type of progression, initial form of the disease, EDSS and number of relapses; disease-modifying treatment and reasons for treatment withdrawal; personal and family history of cancer; and incidence and mortality. Analysis of patients in La Rioja diagnosed with MS (according to Poser criteria or the 2005 McDonald criteria) during a 10-year period (2001-2011). Data were collected from hospital records, multiple sclerosis associations, and personal records kept by neurologists. The MS prevalence rate in La Rioja is 65 patients/100 000 inhabitants with an incidence rate of 3.5 cases/100 000 residents per year. Relapsing-remitting MS is present in 67.6% of the patient total. Mean age of onset is 20-29 years (range, 12 to 70). Most EDSS scores were mostly ≤ 2. Untreated MS cases account for 47.6% of the total and the most commonly used therapy is interferon. We detected 4 haematological tumours and 7 families with multiple members affected by MS. Prevalence and incidence are similar to those found in other regions Spain. The average age at onset age for primary progressive MS is slightly higher than in other papers (40-49 years). In families with multiple patients, MS may be more aggressive. Disability in these patients remains very severe. We require more epidemiology studies with a variety of data gathering methods to support findings for prevalence obtained in different provinces. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Depressive Symptoms Correlate with Disability and Disease Course in Multiple Sclerosis Patients: An Italian Multi-Center Study Using the Beck Depression Inventory.

PubMed

Solaro, C; Trabucco, E; Signori, A; Martinelli, V; Radaelli, M; Centonze, D; Rossi, S; Grasso, M G; Clemenzi, A; Bonavita, S; D'Ambrosio, A; Patti, F; D'Amico, E; Cruccu, G; Truini, A

2016-01-01

Depression occurs in about 50% of patients with multiple sclerosis. The aims of this study was to investigate the prevalence of depressive symptoms in a multicenter MS population using the Beck Depression Inventory II (BDI II) and to identify possible correlations between the BDI II score and demographic and clinical variables. Data were collected in a multi-center, cross-sectional study over a period of six months in six MS centers in Italy using BDI II. 1,011 MS patients participated in the study. 676 subjects were female, with a mean age of 34 years (SD 10.8), mean EDSS of 3.3 (0-8.5) and mean disease duration of 10.3 years (range 1-50 years). 668 (%) subjects scored lower than 14 on the BDI II and 343 (33.9%) scored greater than 14 (14 cut-off score). For patients with BDI>14 multivariate analysis showed a significant difference between EDSS and disease course. BDI II scores for subjects with secondary progressive (SP) MS were significantly different from primary progressive (PP) patients (p < 0.001) but similar to relapsing-remitting (RR) patients. Considering subjects with moderate to severe depressive symptoms (BDI II score from 20-63), in relation to disease course, 11.7% (83/710) had RR MS, 40.7% (96/236) SP and 13.6% (6/44) PP. Using the BDI II, 30% of the current sample had depressive symptoms. BDI II score correlates with disability and disease course, particularly in subjects with SP MS. The BDI II scale can be a useful tool in clinical practice to screen depressive symptoms in people with MS.

Empirical mode decomposition processing to improve multifocal-visual-evoked-potential signal analysis in multiple sclerosis

PubMed Central

2018-01-01

Objective To study the performance of multifocal-visual-evoked-potential (mfVEP) signals filtered using empirical mode decomposition (EMD) in discriminating, based on amplitude, between control and multiple sclerosis (MS) patient groups, and to reduce variability in interocular latency in control subjects. Methods MfVEP signals were obtained from controls, clinically definitive MS and MS-risk progression patients (radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS)). The conventional method of processing mfVEPs consists of using a 1–35 Hz bandpass frequency filter (XDFT). The EMD algorithm was used to decompose the XDFT signals into several intrinsic mode functions (IMFs). This signal processing was assessed by computing the amplitudes and latencies of the XDFT and IMF signals (XEMD). The amplitudes from the full visual field and from ring 5 (9.8–15° eccentricity) were studied. The discrimination index was calculated between controls and patients. Interocular latency values were computed from the XDFT and XEMD signals in a control database to study variability. Results Using the amplitude of the mfVEP signals filtered with EMD (XEMD) obtains higher discrimination index values than the conventional method when control, MS-risk progression (RIS and CIS) and MS subjects are studied. The lowest variability in interocular latency computations from the control patient database was obtained by comparing the XEMD signals with the XDFT signals. Even better results (amplitude discrimination and latency variability) were obtained in ring 5 (9.8–15° eccentricity of the visual field). Conclusions Filtering mfVEP signals using the EMD algorithm will result in better identification of subjects at risk of developing MS and better accuracy in latency studies. This could be applied to assess visual cortex activity in MS diagnosis and evolution studies. PMID:29677200

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

PubMed Central

Miljković, Djordje; Spasojević, Ivan

2013-01-01

Abstract The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. Antioxid. Redox Signal. 19, 2286–2334. PMID:23473637

Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 1-Mechanisms, Efficacy, and Safety.

PubMed

McNamara, C; Sugrue, G; Murray, B; MacMahon, P J

2017-09-01

Imaging for the diagnosis and follow-up of patients with suspected or confirmed multiple sclerosis is a common scenario for many general radiologists and subspecialty neuroradiologists. The field of MS therapeutics has rapidly evolved with multiple new agents now being used in routine clinical practice. To provide an informed opinion in discussions concerning newer MS agents, radiologists must have a working understanding of the strengths and limitations of the various novel therapies. The role of imaging in MS has advanced beyond monitoring and surveillance of disease activity to include treatment complications. An understanding of the new generation of MS drugs in conjunction with the key role that MR imaging plays in the detection of disease progression, opportunistic infections, and drug-related adverse events is of vital importance to the radiologist and clinical physician alike. Radiologists are in a unique position to detect many of the described complications well in advance of clinical symptoms. Part 1 of this review outlines recent developments in the treatment of MS and discusses the published clinical data on the efficacy and safety of the currently approved and emerging therapies in this condition as they apply to the radiologist. Part 2 will cover pharmacovigilance and the role the neuroradiologist plays in monitoring patients for signs of opportunistic infection and/or disease progression. © 2017 by American Journal of Neuroradiology.

Iron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping

PubMed Central

Stüber, Carsten; Pitt, David; Wang, Yi

2016-01-01

Iron is considered to play a key role in the development and progression of Multiple Sclerosis (MS). In particular, iron that accumulates in myeloid cells after the blood-brain barrier (BBB) seals may contribute to chronic inflammation, oxidative stress and eventually neurodegeneration. Magnetic resonance imaging (MRI) is a well-established tool for the non-invasive study of MS. In recent years, an advanced MRI method, quantitative susceptibility mapping (QSM), has made it possible to study brain iron through in vivo imaging. Moreover, immunohistochemical investigations have helped defining the lesional and cellular distribution of iron in MS brain tissue. Imaging studies in MS patients and of brain tissue combined with histological studies have provided important insights into the role of iron in inflammation and neurodegeneration in MS. PMID:26784172

Human single-neuron responses at the threshold of conscious recognition

PubMed Central

Quiroga, R. Quian; Mukamel, R.; Isham, E. A.; Malach, R.; Fried, I.

2008-01-01

We studied the responses of single neurons in the human medial temporal lobe while subjects viewed familiar faces, animals, and landmarks. By progressively shortening the duration of stimulus presentation, coupled with backward masking, we show two striking properties of these neurons. (i) Their responses are not statistically different for the 33-ms, 66-ms, and 132-ms stimulus durations, and only for the 264-ms presentations there is a significantly higher firing. (ii) These responses follow conscious perception, as indicated by the subjects' recognition report. Remarkably, when recognized, a single snapshot as brief as 33 ms was sufficient to trigger strong single-unit responses far outlasting stimulus presentation. These results suggest that neurons in the medial temporal lobe can reflect conscious recognition by “all-or-none” responses. PMID:18299568

Recent progress in microchip electrophoresis-mass spectrometry.

PubMed

Kitagawa, Fumihiko; Otsuka, Koji

2011-06-25

This review highlights the methodological and instrumental developments in microchip electrophoresis (MCE)-mass spectrometry (MS) from 1997. In MCE-MS, the development of ionization interface is one of the most important issues to realize highly sensitive detection and high separation efficiency. Among several interfaces, electrospray ionization (ESI) has been mainly employed to MCE-MS since a simple structure of the ESI interface is suitable for coupling with the microchips. Although the number of publications is still limited, laser desorption ionization (LDI) interface has also been developed for MCE-MS. The characteristics of the ESI and LDI interfaces applied to the electrophoresis microchips are presented in this review. The scope of applications in MCE-MS covers mainly biogenic compounds such as bioactive amines, peptides, tryptic digests and proteins. This review provides a comprehensive table listing the applications in MCE-MS. Copyright © 2010 Elsevier B.V. All rights reserved.

Marginal Structural Cox Models for Estimating the Association Between β-Interferon Exposure and Disease Progression in a Multiple Sclerosis Cohort

PubMed Central

Karim, Mohammad Ehsanul; Gustafson, Paul; Petkau, John; Zhao, Yinshan; Shirani, Afsaneh; Kingwell, Elaine; Evans, Charity; van der Kop, Mia; Oger, Joel; Tremlett, Helen

2014-01-01

Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the “real-world” clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995–2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed “normalized stabilized” weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings. PMID:24939980

Markers of oxidative/nitrative damage of plasma proteins correlated with EDSS and BDI scores in patients with secondary progressive multiple sclerosis.

PubMed

Morel, Agnieszka; Bijak, Michał; Niwald, Marta; Miller, Elżbieta; Saluk, Joanna

2017-11-01

The objective of the present study was to evaluate oxidative/nitrative stress in the plasma of 50 patients suffering from the secondary progressive course of multiple sclerosis (MS), and to verify its correlation with physical and mental disability as assessed by the Expanded Disability Status Scale (EDSS), and the Beck Depression Inventory (BDI). Oxidative and nitrative damage to proteins was determined by the level of carbonyl groups and 3-nitrotyrosine using ELISA test. Based on the reaction with Ellman's reagent, we estimated the concentration of oxidized thiol groups. Additionally, we measured the level of lipid peroxidation. In plasma drawn from MS patients, we observed a significantly higher level of 3-NT (92%; P < 0.0003), carbonyl groups (29%; P < 0.0001) and thiobarbituric acid reactive substances (73%; P < 0.0001), as well as a lower concentration of thiol groups (33%; P < 0.0001), in comparison to healthy subjects. We noted positive correlations between the level of carbonyl groups or 3-NT and both diagnostic parameters, EDSS and BDI. Negative correlations were observed between concentration of -SH groups and EDSS and BDI. Our results indicate that impaired red-ox balance can significantly promote neurodegeneration in secondary progressive MS.

Progressive decline of decision-making performances during multiple sclerosis.

PubMed

Simioni, Samanta; Ruffieux, Christiane; Kleeberg, Joerg; Bruggimann, Laure; du Pasquier, Renaud A; Annoni, Jean-Marie; Schluep, Myriam

2009-03-01

The purpose of this study was to evaluate longitudinally, using the Iowa Gambling Task (IGT), the dynamics of decision-making capacity at a two-year interval (median: 2.1 years) in a group of patients with multiple sclerosis (MS) (n = 70) and minor neurological disability [Expanded Disability Status Scale (EDSS) < or = 2.5 at baseline]. Cognition (memory, executive functions, attention), behavior, handicap, and perceived health status were also investigated. Standardized change scores [(score at retest-score at baseline)/standard deviation of baseline score] were computed. Results showed that IGT performances decreased from baseline to retest (from 0.3, SD = 0.4 to 0.1, SD = 0.3, p = .005). MS patients who worsened in the IGT were more likely to show a decreased perceived health status and emotional well-being (SEP-59; p = .05 for both). Relapsing rate, disability progression, cognitive, and behavioral changes were not associated with decreased IGT performances. In conclusion, decline in decision making can appear as an isolated deficit in MS.

Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients.

PubMed

Zinger, Anna; Latham, Sharissa L; Combes, Valery; Byrne, Scott; Barnett, Michael H; Hawke, Simon; Grau, Georges E

2016-12-01

No molecular marker can monitor disease progression and treatment efficacy in multiple sclerosis (MS). Circulating microparticles represent a potential snapshot of disease activity at the blood brain barrier. To profile plasma microparticles by flow cytometry in MS and determine how fingolimod could impact endothelial microparticles production. In non-treated MS patients compared to healthy and fingolimod-treated patients, endothelial microparticles were higher, while B-cell-microparticle numbers were lower. Fingolimod dramatically reduced tumour necrosis factor (TNF)-induced endothelial microparticle release in vitro. Fingolimod restored dysregulated endothelial and B-cell-microparticle numbers, which could serve as a biomarker in MS. © The Author(s), 2016.

Quantitative assessment of multiple sclerosis lesion load using CAD and expert input

NASA Astrophysics Data System (ADS)

Gertych, Arkadiusz; Wong, Alexis; Sangnil, Alan; Liu, Brent J.

2008-03-01

Multiple sclerosis (MS) is a frequently encountered neurological disease with a progressive but variable course affecting the central nervous system. Outline-based lesion quantification in the assessment of lesion load (LL) performed on magnetic resonance (MR) images is clinically useful and provides information about the development and change reflecting overall disease burden. Methods of LL assessment that rely on human input are tedious, have higher intra- and inter-observer variability and are more time-consuming than computerized automatic (CAD) techniques. At present it seems that methods based on human lesion identification preceded by non-interactive outlining by CAD are the best LL quantification strategies. We have developed a CAD that automatically quantifies MS lesions, displays 3-D lesion map and appends radiological findings to original images according to current DICOM standard. CAD is also capable to display and track changes and make comparison between patient's separate MRI studies to determine disease progression. The findings are exported to a separate imaging tool for review and final approval by expert. Capturing and standardized archiving of manual contours is also implemented. Similarity coefficients calculated from quantities of LL in collected exams show a good correlation of CAD-derived results vs. those incorporated as expert's reading. Combining the CAD approach with an expert interaction may impact to the diagnostic work-up of MS patients because of improved reproducibility in LL assessment and reduced time for single MR or comparative exams reading. Inclusion of CAD-generated outlines as DICOM-compliant overlays into the image data can serve as a better reference in MS progression tracking.

Gender differences in self-reported symptom awareness and perceived ability to manage therapy with disease-modifying medication among commercially insured multiple sclerosis patients.

PubMed

Vlahiotis, Anna; Sedjo, Rebecca; Cox, Emily R; Burroughs, Thomas E; Rauchway, Amy; Lich, Rebecca

2010-04-01

Multiple sclerosis (MS) is a chronic, neurodegenerative inflammatory disease that affects approximately 400,000 Americans, the majority of whom are female. Although MS prevalence is higher among females, males are more likely to have a more progressive clinical course. For both genders, use of disease-modifying medications (DMMs) in the clinical management of MS is pivotal in altering the natural course and diminishing progressive disability over time. To evaluate gender differences in self-reported symptom awareness and perceived ability to manage therapy among MS patients taking a DMM. During February 2008, a self-administered, 42-item survey was mailed to 4,700 commercially insured patients taking a DMM to treat MS. Survey items measured self-reported clinical characteristics, symptom awareness, and perceived ability to manage therapy. Bivariate analyses assessed associations of gender with other predictor and outcome variables, including demographic characteristics, clinical disease characteristics, specific DMM used at the time of the survey, self-reported symptom awareness, and perceived ability to manage therapy. Logistic regression analyses further assessed the associations of gender with symptom awareness and perceived ability to manage MS after adjustment for relevant covariates (age at diagnosis, educational level, income, current DMM, type of pharmacy where drug was dispensed, frequency of flare-ups, and clinical course of disease). The response rate was 44.1% (n = 2,074). Of the 2,022 respondents with useable surveys, 80.6% were female; 82.3% had relapsing remitting MS; and 83.1% were taking one of the most commonly used DMMs (intramuscular interferon beta-1a 33.4%, subcutaneous interferon beta-1a 15.9%, and glatiramer acetate 33.8%). Compared with female patients, males were older and a greater proportion had a more progressive clinical course of disease. In multivariate models, female patients were more likely than males to report recognition of a relapse/exacerbation (odds ratio [OR] = 1.37, 95% CI = 1.03-1.82) and to report knowing what to do when experiencing a relapse/exacerbation (OR = 1.34, 95% CI = 1.01- 1.77) or if they missed a dose of medication (OR = 1.78, 95% CI = 1.08-2.43). Females were also more likely to report awareness of treatment options (OR = 1.48, 95% CI = 1.07-2.07) and to think that DMMs were helping their MS (OR = 1.32, 95% CI = 1.02-1.77). Female MS patients report better awareness of disease symptoms and have more positive perceptions of their ability to manage therapy with DMMs than male MS patients. These findings suggest that male MS patients may require additional education and support to manage their disease and therapy needs. Knowledge of these gender differences potentially could help managed care organizations to improve therapy adherence by guiding gender-specific patient support programs.

Prismatic displacement effect of progressive multifocal glasses on reaction time and accuracy in elderly people

PubMed Central

Ellison, Ashton C; Campbell, A John; Robertson, M Clare; Sanderson, Gordon F

2014-01-01

Background Multifocal glasses (bifocals, trifocals, and progressives) increase the risk of falling in elderly people, but how they do so is unclear. To explain why glasses with progressive addition lenses increase the risk of falls and whether this can be attributed to false projection, this study aimed to 1) map the prismatic displacement of a progressive lens, and 2) test whether this displacement impaired reaction time and accuracy. Methods The reaction times of healthy ≥75-year-olds (31 participants) were measured when grasping for a bar and touching a black line. Participants performed each test twice, wearing their progressives and new, matched single vision (distance) glasses in random order. The line and bar targets were positioned according to the maximum and minimum prismatic displacement effect through the progressive lens, mapped using a focimeter. Results Progressive spectacle lenses have large areas of prismatic displacement in the central visual axis and edges. Reaction time was faster for progressives compared with single vision glasses with a centrally-placed horizontal grab bar (mean difference 101 ms, P=0.011 [repeated measures analysis]) and a horizontal black line placed 300 mm below center (mean difference 80 ms, P=0.007). There was no difference in accuracy between the two types of glasses. Conclusion Older people appear to adapt to the false projection of progressives in the central visual axis. This adaptation means that swapping to new glasses or a large change in prescription may lead to a fall. Frequently updating glasses may be more beneficial. PMID:24872674

Prospective memory impairment in multiple sclerosis: a review.

PubMed

Rouleau, Isabelle; Dagenais, Emmanuelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

2017-08-04

Multiple sclerosis (MS) is a progressive disease of the central nervous system affecting information processing speed, episodic memory, attention, and executive functions. MS patients also often report prospective memory (PM) failures that directly impact their functional autonomy, including professional and social life. The purpose of this paper was to review the literature concerning the assessment and remediation of PM deficits in MS. The literature pertaining to PM impairment in MS was carefully reviewed using PubMed, PsyINFO, and Google Scholar, as well as cross-references from the articles published on this topic. Since PM rehabilitation in MS patients is still in its infancy, this review mainly focuses on studies that have directly assessed PM through various measures including questionnaires, standardized clinical tests, and experimental procedures. This literature review confirms the presence of PM deficits in MS patients, even in the early stages of the disease. A further need for controlled studies on PM assessment and PM interventions in patients with MS is stressed.

Peptidomics of Three Bothrops Snake Venoms: Insights Into the Molecular Diversification of Proteomes and Peptidomes*

PubMed Central

Tashima, Alexandre K.; Zelanis, André; Kitano, Eduardo S.; Ianzer, Danielle; Melo, Robson L.; Rioli, Vanessa; Sant'anna, Sávio S.; Schenberg, Ana C. G.; Camargo, Antônio C. M.; Serrano, Solange M. T.

2012-01-01

Snake venom proteomes/peptidomes are highly complex and maintenance of their integrity within the gland lumen is crucial for the expression of toxin activities. There has been considerable progress in the field of venom proteomics, however, peptidomics does not progress as fast, because of the lack of comprehensive venom sequence databases for analysis of MS data. Therefore, in many cases venom peptides have to be sequenced manually by MS/MS analysis or Edman degradation. This is critical for rare snake species, as is the case of Bothrops cotiara (BC) and B. fonsecai (BF), which are regarded as near threatened with extinction. In this study we conducted a comprehensive analysis of the venom peptidomes of BC, BF, and B. jararaca (BJ) using a combination of solid-phase extraction and reversed-phase HPLC to fractionate the peptides, followed by nano-liquid chromatography-tandem MS (LC-MS/MS) or direct infusion electrospray ionization-(ESI)-MS/MS or MALDI-MS/MS analyses. We detected marked differences in the venom peptidomes and identified peptides ranging from 7 to 39 residues in length by de novo sequencing. Forty-four unique sequences were manually identified, out of which 30 are new peptides, including 17 bradykinin-potentiating peptides, three poly-histidine-poly-glycine peptides and interestingly, 10 l-amino acid oxidase fragments. Some of the new bradykinin-potentiating peptides display significant bradykinin potentiating activity. Automated database search revealed fragments from several toxins in the peptidomes, mainly from l-amino acid oxidase, and allowed the determination of the peptide bond specificity of proteinases and amino acid occurrences for the P4-P4′ sites. We also demonstrate that the venom lyophilization/resolubilization process greatly increases the complexity of the peptidome because of the imbalance caused to the venom proteome and the consequent activity of proteinases on venom components. The use of proteinase inhibitors clearly showed different outcomes in the peptidome characterization and suggested that degradomic-peptidomic analysis of snake venoms is highly sensitive to the conditions of sampling procedures. PMID:22869554

Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

PubMed

Oeckl, Patrick; Steinacker, Petra; von Arnim, Christine A F; Straub, Sarah; Nagl, Magdalena; Feneberg, Emily; Weishaupt, Jochen H; Ludolph, Albert C; Otto, Markus

2014-11-07

The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

PubMed Central

Pender, Michael P; Burrows, Scott R

2014-01-01

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. PMID:25505955

"A Group of Me's": Adult Learning through Group Process: The Experiences of Participants in a Teleconference Delivered Multiple Sclerosis Fatigue Management Program

ERIC Educational Resources Information Center

Preissner, Katharine L.

2013-01-01

Multiple sclerosis (MS) is a chronic, progressive neurological disorder that affects approximately 2.1 million people worldwide. Fatigue is one of the most common and most disabling symptoms of MS. One well-established approach to address fatigue is fatigue management education provided by an occupational therapist. Fatigue management education is…

High intensity interval training for people with multiple sclerosis: A systematic review.

PubMed

Campbell, Evan; Coulter, Elaine H; Paul, Lorna

2018-06-13

Aerobic high intensity interval training (HIIT) is safe in the general population and more efficient in improving fitness than continuous moderate intensity training. The body of literature examining HIIT in multiple sclerosis (MS) is expanding but to date a systematic review has not been conducted. The aim of this review was to investigate the efficacy and safety of HIIT in people with MS. A systematic search was carried out in September 2017 in EMBASE, MEDline, PEDro, CENTRAL and Web of Science Core collections using appropriate keywords and MeSH descriptors. Reference lists of relevant articles were also searched. Articles were eligible for inclusion if they were published in English, used HIIT, and included participants with MS. Quality was assessed using the PEDro scale. The following data were extracted using a standardised form: study design and characteristics, outcome measures, significant results, drop-outs, and adverse events. Seven studies (described by 11 articles) were identified: four randomised controlled trials, one randomised cross-over trial and two cohort studies. PEDro scores ranged from 3 to 8. Included participants (n = 249) were predominantly mildly disabled; one study included only people with progressive MS. Six studies used cycle ergometry and one used arm ergometry to deliver HIIT. One study reported six adverse events, four which could be attributed to the intervention. The other six reported that there were no adverse events. Six studies reported improvements in at least one outcome measure, however there were 60 different outcome measures in the seven studies. The most commonly measured domain was fitness, which improved in five of the six studies measuring aspects of fitness. The only trial not to report positive results included people with progressive and a more severe level of disability (Extended Disability Status Scale 6.0-8.0). HIIT appears to be safe and effective in increasing fitness in people with MS and low levels of disability. Further research is required to explore the effectiveness of HIIT in people with progressive MS and in those with higher levels of disability. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Post-marketing survey on clinical response to interferon beta in relapsing multiple sclerosis: the Roman experience.

PubMed

Pozzilli, C; Prosperini, L; Sbardella, E; De Giglio, L; Onesti, E; Tomassini, V

2005-12-01

Safety, tolerability and efficacy profiles of interferon beta (IFNbeta) therapy in relapsing multiple sclerosis (MS) has been widely verified both in trial settings and in daily clinical practice. However, for a variable percentage of treated patients, it remains only partially effective. In this study, we reported the post-marketing experience of the efficacy of IFNbeta therapy for a large cohort of MS patients regularly attending the MS Outpatient Clinic of "La Sapienza University" in Rome. In this cohort we also sought clinical and paraclinical variables responsible for the clinical course of MS during IFNbeta therapy. Patients that received treatment with one of the IFNbeta formulations for at least 1 year were included. Clinical outcomes (i. e., relapses and disability score) were monitored throughout the entire study period. Magnetic resonance imaging (MRI) scans were performed twice for each subject: at baseline and after 1 year of therapy. The occurrence of more than one relapse during the study period or a sustained disability progression in the Expanded Disability Status Scale (EDSS) score were considered as criteria for the definition of suboptimal clinical response to IFNbeta therapy. During IFNbeta therapy (number of patients 242, mean length of treatment 4.3+/-2.3 years) a reduction in the annualised relapse rate of 59% (p<0.001) was observed. Eighty-six patients (35%) fulfilled the criterion for defining "suboptimal responder" on the basis of relapses, and 69 (28.5%) did the same on the basis of EDSS sustained progression. Twenty-seven (11.1%) patients showed both an EDSS progression and two or more relapses. The presence of T1-enhancing lesions and new T2 hyperintense lesions on the scan performed after the first year of therapy were the best MRI features associated with both the occurrence of relapses during the treatment period (OR for enhancing lesions and relapses 3.6; OR for new T2 lesion and relapses 2.8). The present post-marketing experience confirms the efficacy of IFNbeta in modifying the natural course of MS and encourages the use of paraclinical variables measuring subclinical disease activity as surrogate markers to monitor the clinical course of MS during IFNbeta therapy.

Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis

PubMed Central

Amadio, Susanna; Parisi, Chiara; Piras, Eleonora; Fabbrizio, Paola; Apolloni, Savina; Montilli, Cinzia; Luchetti, Sabina; Ruggieri, Serena; Gasperini, Claudio; Laghi-Pasini, Franco; Battistini, Luca; Volonté, Cinzia

2017-01-01

Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2′(3′)-O-(4 Benzoylbenzoyl)adenosine 5′-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS. PMID:29187851

A Catalogue of Altered Salivary Proteins Secondary to Invasive Ductal Carcinoma: A Novel In Vivo Paradigm to Assess Breast Cancer Progression

PubMed Central

Streckfus, Charles F.; Bigler, Lenora

2016-01-01

The objective of this manuscript is to introduce a catalogue of salivary proteins that are altered secondary to carcinoma of the breast. The catalogue of salivary proteins is a compilation of twenty years of research by the authors and consists of 233 high and low abundant proteins which have been identified by LC-MS/MS mass spectrometry, 2D-gel analysis and by enzyme-linked immunosorbent assay. The body of research suggests that saliva is a fluid suffused with solubilized by-products of oncogenic expression and that these proteins may be useful in the study of breast cancer progress, treatment efficacy and the tailoring of individualized patient care. PMID:27477923

Antibody-Mediated Targeting of Alpha PDGF Receptor to Inhibit the Progression of Skeletal Micro-Metastases

DTIC Science & Technology

2012-10-01

8217 Affiliatio athology an e, Philadelp ponding Au ysiology, D MS 488, P 2-2299; E-m .1158/1078- American A ancer Respose : Platelet-derived growth factor...their metastatic growth. The resulting increase in tu- ass will recruit and activate a progressively higher er of osteoclasts, thereby generating a self

Multiple sclerosis.

PubMed

Files, Daniel Kane; Jausurawong, Tani; Katrajian, Ruba; Danoff, Robert

2015-06-01

Multiple sclerosis (MS) is a chronic, debilitating disease that can have devastating effects. Presentation varies widely in symptoms, pace, and progression. In addition to a thorough history and physical examination, diagnostic tools required to diagnose MS and exclude other diagnoses include MRI, evoked potential testing, and cerebrospinal fluid analysis. Although the disease is not curable presently, quality of life can be improved by minimizing the frequency and severity of disease burden. Disease modification, symptom management, preservation of function, and treatment of psychosocial issues are paramount to enhance the quality of life for the patient affected with MS. Copyright © 2015 Elsevier Inc. All rights reserved.

Relationships between trunk performance, gait and postural control in persons with multiple sclerosis.

PubMed

Freund, Jane E; Stetts, Deborah M; Vallabhajosula, Srikant

2016-06-30

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system. Compared to healthy individuals, persons with multiple sclerosis (PwMS) have increased postural sway in quiet stance, decreased gait speed and increased fall incidence. Trunk performance has been implicated in postural control, gait dysfunction, and fall prevention in older adults. However, the relationship of trunk performance to postural control and gait has not been adequately studied in PwMS. To compare trunk muscle structure and performance in PwMS to healthy age and gendered-matched controls (HC); to determine the effects of isometric trunk endurance testing on postural control in both populations; and to determine the relationship of trunk performance with postural control, gait and step activity in PwMS. Fifteen PwMS and HC completed ultrasound imaging of trunk muscles, 10 m walk test, isometric trunk endurance tests, and postural sway test. Participants wore a step activity monitor for 7 days. PwMS had worse isometric trunk endurance compared to HC. PwMS trunk flexion endurance negatively correlated to several postural control measures and positively correlated to gait speed and step activity. Clinicians should consider evaluation and interventions directed at impaired trunk endurance in PwMS.

Multiple Sclerosis and Obesity: Possible Roles of Adipokines

PubMed Central

Guerrero-García, José de Jesús; Márquez-Aguirre, Ana Laura

2016-01-01

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS. PMID:27721574

Investigations on aberrant glycosylation of glycosphingolipids in colorectal cancer tissues using liquid chromatography and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS).

PubMed

Holst, Stephanie; Stavenhagen, Kathrin; Balog, Crina I A; Koeleman, Carolien A M; McDonnell, Liam M; Mayboroda, Oleg A; Verhoeven, Aswin; Mesker, Wilma E; Tollenaar, Rob A E M; Deelder, André M; Wuhrer, Manfred

2013-11-01

Cancer is a leading cause of death and alterations of glycosylation are characteristic features of malignant cells. Colorectal cancer is one of the most common cancers and its exact causes and biology are not yet well understood. Here, we compared glycosylation profiles of colorectal tumor tissues and corresponding control tissues of 13 colorectal cancer patients to contribute to the understanding of this cancer. Using MALDI-TOF(/TOF)-MS and 2-dimensional LC-MS/MS we characterized enzymatically released and 2-aminobenzoic acid labeled glycans from glycosphingolipids. Multivariate data analysis revealed significant differences between tumor and corresponding control tissues. Main discriminators were obtained, which represent the overall alteration in glycosylation of glycosphingolipids during colorectal cancer progression, and these were found to be characterized by (1) increased fucosylation, (2) decreased acetylation, (3) decreased sulfation, (4) reduced expression of globo-type glycans, as well as (5) disialyl gangliosides. The findings of our current research confirm former reports, and in addition expand the knowledge of glycosphingolipid glycosylation in colorectal cancer by revealing new glycans with discriminative power and characteristic, cancer-associated glycosylation alterations. The obtained discriminating glycans can contribute to progress the discovery of biomarkers to improve diagnostics and patient treatment.

Investigations on Aberrant Glycosylation of Glycosphingolipids in Colorectal Cancer Tissues Using Liquid Chromatography and Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry (MALDI-TOF-MS)*

PubMed Central

Holst, Stephanie; Stavenhagen, Kathrin; Balog, Crina I. A.; Koeleman, Carolien A. M.; McDonnell, Liam M.; Mayboroda, Oleg A.; Verhoeven, Aswin; Mesker, Wilma E.; Tollenaar, Rob A. E. M.; Deelder, André M.; Wuhrer, Manfred

2013-01-01

Cancer is a leading cause of death and alterations of glycosylation are characteristic features of malignant cells. Colorectal cancer is one of the most common cancers and its exact causes and biology are not yet well understood. Here, we compared glycosylation profiles of colorectal tumor tissues and corresponding control tissues of 13 colorectal cancer patients to contribute to the understanding of this cancer. Using MALDI-TOF(/TOF)-MS and 2-dimensional LC-MS/MS we characterized enzymatically released and 2-aminobenzoic acid labeled glycans from glycosphingolipids. Multivariate data analysis revealed significant differences between tumor and corresponding control tissues. Main discriminators were obtained, which represent the overall alteration in glycosylation of glycosphingolipids during colorectal cancer progression, and these were found to be characterized by (1) increased fucosylation, (2) decreased acetylation, (3) decreased sulfation, (4) reduced expression of globo-type glycans, as well as (5) disialyl gangliosides. The findings of our current research confirm former reports, and in addition expand the knowledge of glycosphingolipid glycosylation in colorectal cancer by revealing new glycans with discriminative power and characteristic, cancer-associated glycosylation alterations. The obtained discriminating glycans can contribute to progress the discovery of biomarkers to improve diagnostics and patient treatment. PMID:23878401

Multiple sclerosis (MS) for the urologist: What should urologists know about MS?

PubMed

Aharony, Shachar; Lam, Ornella; Lapierre, Yves; Corcos, Jacques

2016-02-01

Multiple sclerosis (MS) is a unique central nervous system (CNS) inflammatory disease with a broad spectrum of clinical presentations, which are time- and disease progression-related. It usually affects young adults, with a female predominance of 3:1. Men are more likely to develop symptoms at a slightly older age with a more progressive disease course. Diagnosis relies on a combination of clinical, radiological, and laboratory investigations, with a central role of magnetic resonance imaging (MRI). Although the exact etiology is still obscure, the leading hypothesis behind MS relapses is acute inflammatory attacks on CNS myelin and axons. This complex process involves B and T cells together with macrophages and microglia. Genetic and environmental factors are thought to be major contributors to the disease's evolution. MS therapies consist of long-term (immunomodulatory) management, focusing on disease modification, and short-term symptomatic control. Symptomatic treatment includes pharmacological and non-pharmacological methods to protect function and restore quality of life (QoL). The introduction and development of disease-modifying medications provide opportunities to change the face of this disease, enhancing QoL over the long-term. Interferon (INF) and Glatiramer acetate (GLAT) represent first line medications with limited effect and relatively fair safety profile. Newer medications with improved efficacy along with a more hazardous side effect profile are now considered second line therapy. The present review summarizes current knowledge of this frequent disease. Urologists must acquire a deeper understanding for better integration of practice recommendations. © 2015 Wiley Periodicals, Inc.

Treatment strategies for multiple sclerosis: When to start, when to change, when to stop?

PubMed Central

Gajofatto, Alberto; Benedetti, Maria Donata

2015-01-01

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies. PMID:26244148

Optical Coherence Tomography as a Biomarker for Diagnosis, Progression, and Prognosis of Neurodegenerative Diseases

PubMed Central

Otin, Sofia; Fuertes, Maria I.; Vilades, Elisa; Gracia, Hector; Ara, Jose R.; Alarcia, Raquel; Polo, Vicente; Larrosa, Jose M.; Pablo, Luis E.

2016-01-01

Neurodegenerative diseases present a current challenge for accurate diagnosis and for providing precise prognostic information. Developing imaging biomarkers for multiple sclerosis (MS), Parkinson disease (PD), and Alzheimer's disease (AD) will improve the clinical management of these patients and may be useful for monitoring treatment effectiveness. Recent research using optical coherence tomography (OCT) has demonstrated that parameters provided by this technology may be used as potential biomarkers for MS, PD, and AD. Retinal thinning has been observed in these patients and new segmentation software for the analysis of the different retinal layers may provide accurate information on disease progression and prognosis. In this review we analyze the application of retinal evaluation using OCT technology to provide better understanding of the possible role of the retinal layers thickness as biomarker for the detection of these neurodegenerative pathologies. Current OCT analysis of the retinal nerve fiber layer and, specially, the ganglion cell layer thickness may be considered as a good biomarker for disease diagnosis, severity, and progression. PMID:27840739

Reduced serum myostatin concentrations associated with genetic muscle disease progression.

PubMed

Burch, Peter M; Pogoryelova, Oksana; Palandra, Joe; Goldstein, Richard; Bennett, Donald; Fitz, Lori; Guglieri, Michela; Bettolo, Chiara Marini; Straub, Volker; Evangelista, Teresinha; Neubert, Hendrik; Lochmüller, Hanns; Morris, Carl

2017-03-01

Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

Total lymphoid irradiation for multiple sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devereux, C.K.; Vidaver, R.; Hafstein, M.P.

1988-01-01

Although chemical immunosuppression has been shown to benefit patients with chronic progressive multiple sclerosis (MS), it appears that chemotherapy has an appreciable oncogenic potential in patients with multiple sclerosis. Accordingly, we developed a modified total lymphoid irradiation (TLI) regimen designed to reduce toxicity and applied it to a randomized double blind trial of TLI or sham irradiation in MS. Standard TLI regimens were modified to reduce dose to 1,980 rad, lowering the superior mantle margin to midway between the thyroid cartilage and angle of the mandible (to avert xerostomia) and the lower margin of the mantle field to the inferiormore » margin of L1 (to reduce gastrointestinal toxicity by dividing abdominal radiation between mantle and inverted Y), limiting spinal cord dose to 1,000 rad by custom-made spine blocks in the mantle and upper 2 cm of inverted Y fields, and also protecting the left kidney even if part of the spleen were shielded. Clinical efficacy was documented by the less frequent functional scale deterioration of 20 TLI treated patients with chronic progressive MS compared to to 20 sham-irradiated progressive MS patients after 12 months (16% versus 55%, p less than 0.03), 18 months (28% versus 63%, p less than 0.03), and 24 months (44% versus 74%, N.S.). Therapeutic benefit during 3 years follow-up was related to the reduction in lymphocyte count 3 months post-irradiation (p less than 0.02). Toxicity was generally mild and transient, with no instance of xerostomia, pericarditis, herpes zoster, or need to terminate treatment in TLI patients. However, menopause was induced in 2 patients and staphylococcal pneumonia in one.« less

Prenatal maternal immune activation increases anxiety- and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis.

PubMed

Majidi-Zolbanin, J; Doosti, M-H; Kosari-Nasab, M; Salari, A-A

2015-05-21

Multiple sclerosis (MS) is thought to result from a combination of genetics and environmental factors. Several lines of evidence indicate that significant prevalence of anxiety and depression-related disorders in MS patients can influence the progression of the disease. Although we and others have already reported the consequences of prenatal maternal immune activation on anxiety and depression, less is known about the interplay between maternal inflammation, MS and gender. We here investigated the effects of maternal immune activation with Poly I:C during mid-gestation on the progression of clinical symptoms of experimental autoimmune encephalomyelitis (EAE; a mouse model of MS), and then anxiety- and depressive-like behaviors in non-EAE and EAE-induced offspring were evaluated. Stress-induced corticosterone and tumor necrosis factor-alpha (TNF-α) levels in EAE-induced offspring were also measured. Maternal immune activation increased anxiety and depression in male offspring, but not in females. This immune challenge also resulted in an earlier onset of the EAE clinical signs in male offspring and enhanced the severity of the disease in both male and female offspring. Interestingly, the severity of the disease was associated with increased anxiety/depressive-like behaviors and elevated corticosterone or TNF-α levels in both sexes. Overall, these data suggest that maternal immune activation with Poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors, and the clinical symptoms of EAE in a sex-dependent manner in non-EAE or EAE-induced offspring. Finally, the progression of EAE in offspring seems to be linked to maternal immune activation-induced dysregulation in neuro-immune-endocrine system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Fatty acid composition indicates two types of metabolic syndrome independent of clinical and laboratory parameters.

PubMed

Žák, A; Burda, M; Vecka, M; Zeman, M; Tvrzická, E; Staňková, B

2014-01-01

Dietary composition and metabolism of fatty acids (FA) influence insulin resistance, atherogenic dyslipidemia and other components of the metabolic syndrome (MS). It is known that patients with MS exhibit a heterogeneous phenotype; however, the relationships of individual FA to MS components have not yet been consistently studied. We examined the plasma phosphatidylcholine FA composition of 166 individuals (68F/98M) with MS and of 188 (87F/101M) controls. Cluster analysis of FA divided the groups into two clusters. In cluster 1, there were 65.7 % of MS patients and 37.8 % of controls, cluster 2 contained 34.3 % of patients and 62.2 % of controls (P<0.001). Those with MS within cluster 1 (MS1) differed from individuals with MS in cluster 2 (MS2) by concentrations of glucose (P<0.05), NEFA (P<0.001), HOMA-IR (P<0.05), and levels of conjugated dienes in LDL (P<0.05). The FA composition in MS1 group differed from MS2 by higher contents of palmitoleic (+30 %), gamma-linolenic (+22 %), dihomo-gamma-linolenic (+9 %) acids and by a lower content of linoleic acid (-25 %) (all P<0.01). These FA patterns are supposed to be connected with the progression and/or impaired biochemical measures of MS (lipolysis, oxidative stress, dysglycidemia, and insulin resistance).

Diagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients.

PubMed

Wattjes, Mike P; Wijburg, Martijn T; Vennegoor, Anke; Witte, Birgit I; Roosendaal, Stefan D; Sanchez, Esther; Liu, Yaou; Martins Jarnalo, Carine O; Richert, Nancy D; Uitdehaag, Bernard Mj; Barkhof, Frederik; Killestein, Joep

2016-08-01

In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML). To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability. In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions (n = 21) or new MS lesions (n = 20) or no new lesions (n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated. Overall sensitivity and specificity for the detection of new lesions, regardless of the nature of the lesions, were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate. The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate. © The Author(s), 2015.

[Chronically ill and unemployed? A review on vocational status in multiple sclerosis].

PubMed

Kern, S; Kühn, M; Ziemssen, T

2013-02-01

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. It is characterised by a chronic progressive course with far reaching implications on the patient's private and professional life. Based on the current literature, employment status is analysed in relation to disease-specific, therapeutic, psychosocial, and socioeconomic factors. A special emphasis is placed on the vocational status of MS patients in Germany. According national and international studies, around 40 % of all MS patients are currently unemployed. Main reasons for early retirement are disease-specific factors such as impaired mobility, disability in the upper extremities, fatigue, and cognitive impairment. According to the German Multiple Sclerosis Registry (GMSR), these symptoms are still insufficiently treated. In patients with minor motoric impairment (EDSS ≤ 3.0), depressive symptoms seem to have a major impact on employment status. Disease progression, older age at diagnosis, and hard physical work are negative predictors in terms of employment situation. The lack of flexible working hours, the inability to have flexible resting times at work, a lack of understanding from colleagues and employers as well as the personal attitude were main non-disease-specific reasons for early retirement. The current knowledge on the vocational status in MS is mainly based on international studies (e. g., Scandinavia, England, USA, Australia, MSIF Survey). For Germany, only the GMSR supports significant information on the employment status of MS patients. According to the GMSR, ataxia, fatigue and cognitive dysfunction are still insufficiently treated - a situation that is at least partly due to insufficient treatment options. Comprehensive studies that focus on a broad range of possible influencing factors on vocational status of German MS patients are currently lacking. © Georg Thieme Verlag KG Stuttgart · New York.

An automatic quantification system for MS lesions with integrated DICOM structured reporting (DICOM-SR) for implementation within a clinical environment

NASA Astrophysics Data System (ADS)

Jacobs, Colin; Ma, Kevin; Moin, Paymann; Liu, Brent

2010-03-01

Multiple Sclerosis (MS) is a common neurological disease affecting the central nervous system characterized by pathologic changes including demyelination and axonal injury. MR imaging has become the most important tool to evaluate the disease progression of MS which is characterized by the occurrence of white matter lesions. Currently, radiologists evaluate and assess the multiple sclerosis lesions manually by estimating the lesion volume and amount of lesions. This process is extremely time-consuming and sensitive to intra- and inter-observer variability. Therefore, there is a need for automatic segmentation of the MS lesions followed by lesion quantification. We have developed a fully automatic segmentation algorithm to identify the MS lesions. The segmentation algorithm is accelerated by parallel computing using Graphics Processing Units (GPU) for practical implementation into a clinical environment. Subsequently, characterized quantification of the lesions is performed. The quantification results, which include lesion volume and amount of lesions, are stored in a structured report together with the lesion location in the brain to establish a standardized representation of the disease progression of the patient. The development of this structured report in collaboration with radiologists aims to facilitate outcome analysis and treatment assessment of the disease and will be standardized based on DICOM-SR. The results can be distributed to other DICOM-compliant clinical systems that support DICOM-SR such as PACS. In addition, the implementation of a fully automatic segmentation and quantification system together with a method for storing, distributing, and visualizing key imaging and informatics data in DICOM-SR for MS lesions improves the clinical workflow of radiologists and visualizations of the lesion segmentations and will provide 3-D insight into the distribution of lesions in the brain.

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis.

PubMed

Lorente Fernández, L; Monte Boquet, E; Pérez-Miralles, F; Gil Gómez, I; Escutia Roig, M; Boscá Blasco, I; Poveda Andrés, J L; Casanova-Estruch, B

2014-06-01

Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

A simple test of choice stepping reaction time for assessing fall risk in people with multiple sclerosis.

PubMed

Tijsma, Mylou; Vister, Eva; Hoang, Phu; Lord, Stephen R

2017-03-01

Purpose To determine (a) the discriminant validity for established fall risk factors and (b) the predictive validity for falls of a simple test of choice stepping reaction time (CSRT) in people with multiple sclerosis (MS). Method People with MS (n = 210, 21-74y) performed the CSRT, sensorimotor, balance and neuropsychological tests in a single session. They were then followed up for falls using monthly fall diaries for 6 months. Results The CSRT test had excellent discriminant validity with respect to established fall risk factors. Frequent fallers (≥3 falls) performed significantly worse in the CSRT test than non-frequent fallers (0-2 falls). With the odds of suffering frequent falls increasing 69% with each SD increase in CSRT (OR = 1.69, 95% CI: 1.27-2.26, p = <0.001). In regression analysis, CSRT was best explained by sway, time to complete the 9-Hole Peg test, knee extension strength of the weaker leg, proprioception and the time to complete the Trails B test (multiple R 2   =   0.449, p < 0.001). Conclusions A simple low tech CSRT test has excellent discriminative and predictive validity in relation to falls in people with MS. This test may prove useful in documenting longitudinal changes in fall risk in relation to MS disease progression and effects of interventions. Implications for rehabilitation Good choice stepping reaction time (CSRT) is required for maintaining balance. A simple low-tech CSRT test has excellent discriminative and predictive validity in relation to falls in people with MS. This test may prove useful documenting longitudinal changes in fall risk in relation to MS disease progression and effects of interventions.

Effect of semen extenders on frozen-thawed boar sperm characteristics and distribution in the female genital tract after deep intrauterine insemination in sows.

PubMed

Noguchi, Michiko; Yoshioka, Koji; Hikono, Hirokazu; Suzuki, Chie; Kikuchi, Kazuhiro

2015-12-01

We compared the effects of extenders of frozen-thawed semen on post-thaw sperm characteristics and the distribution of frozen-thawed spermatozoa in the female genital tract after fixed-timed deep intrauterine insemination (DIUI) in sows. Frozen semen samples were thawed and diluted in either modified Modena solution (mMS) or porcine fertilization medium (PFM) containing theophylline, adenosine and cysteine. Sperm quality, assessed in vitro based on motility using a computer-assisted sperm analyzer and the integrity of the plasma and acrosomal membranes using flow cytometry, was evaluated at 0.5, 1.5, 3 and 6h after thawing. Progressive motility and the percentage of spermatozoa with damaged acrosomal membranes in PFM were significantly better than in mMS throughout the 6h. Sows with estrus synchronized using prostaglandin F2 alpha, equine chorionic gonadotropin and human chorionic gonadotropin (hCG) were inseminated once with mMS- or PFM-diluted 5 × 10(8) frozen-thawed spermatozoa by DIUI at 34 h after the hCG injection. At 4h after DIUI, reproductive tracts were recovered from 30 sows. There were significantly fewer polymorphonuclear leukocytes (PMNs) and more spermatozoa outside PMNs in the uterine horn after PFM treatment than with mMS. When 22 sows were administered DIUI with 10 × 10(8) frozen-thawed spermatozoa at 36 h after hCG, the pregnancy rates did not differ significantly between the mMS- (36%) and PFM- (64%) treated groups. Thus, PFM enhanced progressive sperm motility but increased sperm membrane damage compared with mMS; it also suppressed the migration of PMNs into the uterine lumen. Copyright © 2015 Elsevier B.V. All rights reserved.

A regional consensus recommendation on brain atrophy as an outcome measure in multiple sclerosis.

PubMed

Alroughani, Raed; Deleu, Dirk; El Salem, Khalid; Al-Hashel, Jasem; Alexander, K John; Abdelrazek, Mohamed Assem; Aljishi, Adel; Alkhaboori, Jaber; Al Azri, Faisal; Al Zadjali, Nahida; Hbahbih, Majed; Sokrab, Tag Eldin; Said, Mohamed; Rovira, Àlex

2016-11-24

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory and neurodegenerative processes leading to irreversible neurological impairment. Brain atrophy occurs early in the course of the disease at a rate greater than the general population. Brain volume loss (BVL) is associated with disability progression and cognitive impairment in patients with MS; hence its value as a potential target in monitoring and treating MS is discussed. A group of MS neurologists and neuro-radiologists reviewed the current literature on brain atrophy and discussed the challenges in assessing and implementing brain atrophy measurements in clinical practice. The panel used a voting system to reach a consensus and the votes were counted for the proposed set of questions for cognitive and brain atrophy assessments. The panel of experts was able to identify recent studies, which demonstrated the correlation between BVL and future worsening of disability and cognition. The current evidence revealed that reduction of BVL could be achieved with different disease-modifying therapies (DMTs). BVL provided a better treatment and monitoring strategy when it is combined to the composite measures of "no evidence of disease activity" (NEDA). The panel recommended a set of cognitive assessment tools and MRI methods and software applications that may help in capturing and measuring the underlying MS pathology with high degree of specificity. BVL was considered to be a useful measurement to longitudinally assess disease progression and cognitive function in patients with MS. Brain atrophy measurement was recommended to be incorporated into the concept of NEDA. Consequently, a consensus recommendation was reached in anticipation for implementation of the use of cognitive assessment and brain atrophy measurements on a regional level.

Correlation of Diffusion and Metabolic Alterations in Different Clinical Forms of Multiple Sclerosis

PubMed Central

Hannoun, Salem; Bagory, Matthieu; Durand-Dubief, Francoise; Ibarrola, Danielle; Comte, Jean-Christophe; Confavreux, Christian; Cotton, Francois; Sappey-Marinier, Dominique

2012-01-01

Diffusion tensor imaging (DTI) and MR spectroscopic imaging (MRSI) provide greater sensitivity than conventional MRI to detect diffuse alterations in normal appearing white matter (NAWM) of Multiple Sclerosis (MS) patients with different clinical forms. Therefore, the goal of this study is to combine DTI and MRSI measurements to analyze the relation between diffusion and metabolic markers, T2-weighted lesion load (T2-LL) and the patients clinical status. The sensitivity and specificity of both methods were then compared in terms of MS clinical forms differentiation. MR examination was performed on 71 MS patients (27 relapsing remitting (RR), 26 secondary progressive (SP) and 18 primary progressive (PP)) and 24 control subjects. DTI and MRSI measurements were obtained from two identical regions of interest selected in left and right centrum semioval (CSO) WM. DTI metrics and metabolic contents were significantly altered in MS patients with the exception of N-acetyl-aspartate (NAA) and NAA/Choline (Cho) ratio in RR patients. Significant correlations were observed between diffusion and metabolic measures to various degrees in every MS patients group. Most DTI metrics were significantly correlated with the T2-LL while only NAA/Cr ratio was correlated in RR patients. A comparison analysis of MR methods efficiency demonstrated a better sensitivity/specificity of DTI over MRSI. Nevertheless, NAA/Cr ratio could distinguish all MS and SP patients groups from controls, while NAA/Cho ratio differentiated PP patients from controls. This study demonstrated that diffusivity changes related to microstructural alterations were correlated with metabolic changes and provided a better sensitivity to detect early changes, particularly in RR patients who are more subject to inflammatory processes. In contrast, the better specificity of metabolic ratios to detect axonal damage and demyelination may provide a better index for identification of PP patients. PMID:22479330

Anterior Segment Alterations and Comparative Aqueous Humor Proteomics in the Buphthalmic Rabbit (An American Ophthalmological Society Thesis)

PubMed Central

Edward, Deepak P.; Bouhenni, Rachida

2011-01-01

Purpose To use an integrated proteohistologic approach to gain insight into the anterior segment alterations in the buphthalmic rabbit. Methods Eyes from 2- and 5-year-old buphthalmic and normal rabbits (n=20) were studied histologically. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) of aqueous humor (AH) was used to determine differential protein expression between animal groups. Western blot and immunohistochemistry were performed on selected differentially expressed proteins identified by LC-MS/MS. Results The buphthalmic rabbits manifested a mild clinical phenotype with typical angle anomalies that appeared progressive by histology. Significantly thickened Descemet’s membrane (DM) and anterior lens capsule in all buphthalmic rabbits showed increased fibronectin and collagen-IV immunolabeling. LC-MS/MS applying stringent filtering criteria revealed significant differential expression of several AH proteins in these rabbits. The protein of interest in the 2-year-old group was histidine-rich glycoprotein, and those in the 5-year-old group included alpha-2-HS-glycoprotein, clusterin, apolipoprotein E, interphotoreceptor retinoid-binding protein, transthyretin, cochlin, gelsolin, haptoglobin, hemopexin, and beta-2 microglobulin. The proteomic data for selected proteins was validated by Western blot and immunohistochemistry. A wide range of functional groups were affected by the altered AH proteins. These included extracellular matrix modulation, regulation of apoptosis, oxidative stress, and protein transport. Conclusions Multiple anterior segment alterations were histologically identified in the buphthalmic rabbits that showed progressive changes with age. The differentially expressed AH proteins in these rabbits suggest a multifunctional role for AH in modulating pathologic changes in DM, anterior lens capsule, and the angular meshwork in these animals. PMID:22253484

Preclinical evaluation of the PI3K/Akt/mTOR pathway in animal models of multiple sclerosis

PubMed Central

Mammana, Santa; Bramanti, Placido; Mazzon, Emanuela; Cavalli, Eugenio; Basile, Maria Sofia; Fagone, Paolo; Petralia, Maria Cristina; McCubrey, James Andrew; Nicoletti, Ferdinando; Mangano, Katia

2018-01-01

The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability. PMID:29492193

IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers.

PubMed

Frantzi, Maria; Zoidakis, Jerome; Papadopoulos, Theofilos; Zürbig, Petra; Katafigiotis, Ioannis; Stravodimos, Konstantinos; Lazaris, Andreas; Giannopoulou, Ioanna; Ploumidis, Achilles; Mischak, Harald; Mullen, William; Vlahou, Antonia

2013-09-06

Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1.

Pregnancy and childbirth in a patient with multiple sclerosis: A case report of successful management.

PubMed

Wang, Chun-Kai; Lin, Chi-Kang; Wang, Tun-Jun; Wang, Chen-Yu; Hsu, Po-Chao; Su, Her-Young

2018-06-01

Multiple sclerosis (MS) preferentially affects females of reproductive age, making reproduction an important issue for women with MS. An increased incidence of poor labor progress often results in assisted vaginal delivery or a cesarean section. However, with good pre-pregnancy counseling and management, women with MS can conceive and give birth safely. Here, we present a case of pregnancy with MS, which was carried to term uneventfully and ended with unassisted vaginal delivery. A 36-year-old woman was treated for MS for three years before she conceived. Because of her mild clinical presentation, medication was discontinued when her pregnancy was confirmed. Counseling was completed, and she had a smooth pregnancy course and gave birth vaginally at 38 weeks and two days. Based on this case report, women with mild clinical presentation of MS before pregnancy can conceive and carry successfully to term with no or improved disease presentation. Copyright © 2018. Published by Elsevier B.V.

Defining the clinical course of multiple sclerosis

PubMed Central

Reingold, Stephen C.; Cohen, Jeffrey A.; Cutter, Gary R.; Sørensen, Per Soelberg; Thompson, Alan J.; Wolinsky, Jerry S.; Balcer, Laura J.; Banwell, Brenda; Barkhof, Frederik; Bebo, Bruce; Calabresi, Peter A.; Clanet, Michel; Comi, Giancarlo; Fox, Robert J.; Freedman, Mark S.; Goodman, Andrew D.; Inglese, Matilde; Kappos, Ludwig; Kieseier, Bernd C.; Lincoln, John A.; Lubetzki, Catherine; Miller, Aaron E.; Montalban, Xavier; O'Connor, Paul W.; Petkau, John; Pozzilli, Carlo; Rudick, Richard A.; Sormani, Maria Pia; Stüve, Olaf; Waubant, Emmanuelle; Polman, Chris H.

2014-01-01

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. PMID:24871874

Multiple Sclerosis: Immunopathology and Treatment Update

PubMed Central

Dargahi, Narges; Katsara, Maria; Tselios, Theodore; Androutsou, Maria-Eleni; Matsoukas, John

2017-01-01

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS. PMID:28686222

Clinical Investigation Program Annual Progress Report.

DTIC Science & Technology

1985-09-30

027 78/114 In Vitro Effect of Minoxidil on Collagen Produc- tion by Normal and Scleroderma Fibroblasts (C) (PR...effect of minoxidil on collagen production Dy normal and scleroderma fibroblasts. Previously titled: The use of minoxidil in treating progressive...Svc: (tO) Assoc Investigators: (11) Key Words: scleroderma, minoxidil Thomas P. O’Barr PhD, DAC fibroblasts, collagen Ellen Swanson MS, DAC Don

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

PubMed Central

’t Hart, Bert A.; Dunham, Jordon; Faber, Bart W.; Laman, Jon D.; van Horssen, Jack; Bauer, Jan; Kap, Yolanda S.

2017-01-01

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes. PMID:28744286

Software ion scan functions in analysis of glycomic and lipidomic MS/MS datasets.

PubMed

Haramija, Marko

2018-03-01

Hardware ion scan functions unique to tandem mass spectrometry (MS/MS) mode of data acquisition, such as precursor ion scan (PIS) and neutral loss scan (NLS), are important for selective extraction of key structural data from complex MS/MS spectra. However, their software counterparts, software ion scan (SIS) functions, are still not regularly available. Software ion scan functions can be easily coded for additional functionalities, such as software multiple precursor ion scan, software no ion scan, and software variable ion scan functions. These are often necessary, since they allow more efficient analysis of complex MS/MS datasets, often encountered in glycomics and lipidomics. Software ion scan functions can be easily coded by using modern script languages and can be independent of instrument manufacturer. Here we demonstrate the utility of SIS functions on a medium-size glycomic MS/MS dataset. Knowledge of sample properties, as well as of diagnostic and conditional diagnostic ions crucial for data analysis, was needed. Based on the tables constructed with the output data from the SIS functions performed, a detailed analysis of a complex MS/MS glycomic dataset could be carried out in a quick, accurate, and efficient manner. Glycomic research is progressing slowly, and with respect to the MS experiments, one of the key obstacles for moving forward is the lack of appropriate bioinformatic tools necessary for fast analysis of glycomic MS/MS datasets. Adding novel SIS functionalities to the glycomic MS/MS toolbox has a potential to significantly speed up the glycomic data analysis process. Similar tools are useful for analysis of lipidomic MS/MS datasets as well, as will be discussed briefly. Copyright © 2017 John Wiley & Sons, Ltd.

A prospective study of physical trauma and multiple sclerosis.

PubMed Central

Sibley, W A; Bamford, C R; Clark, K; Smith, M S; Laguna, J F

1991-01-01

During an eight year period 170 multiple sclerosis (MS) patients and 134 controls without physical impairment were followed closely to record all episodes of physical trauma and to measure their effect on exacerbation rate and progression of MS. There was a total of 1407 instances of trauma, which were sorted into various categories. Overall there was no significant correlation between all-traumas and disease activity. There was, however, a statistically significant negative correlation between traumatic episodes and exacerbations in 95 patients who had exacerbations during the programme, due primarily to less activity of the disease during a three month period following surgical procedures and fractures. Electrical injury had a significant positive association with exacerbation using a three month at-risk period, but there were no other significant positive correlations in any other category of trauma, including minor head injuries; there were no cases of head injury with prolonged unconsciousness. There was no linkage between the frequency of trauma and progression of disability. MS patients had two to three times more trauma than controls. PMID:1895121

The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

PubMed

Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

2016-09-01

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

The importance of studying sex differences in disease: The example of multiple sclerosis.

PubMed

Golden, Lisa C; Voskuhl, Rhonda

2017-01-02

To date, scientific research has often focused on one sex, with assumptions that study of the other sex would yield similar results. However, many diseases affect males and females differently. The sex of a patient can affect the risk for both disease susceptibility and progression. Such differences can be brought to the laboratory bench to be investigated, potentially bringing new treatments back to the clinic. This method of research, known as a "bedside to bench to bedside" approach, has been applied to studying sex differences in multiple sclerosis (MS). Females have greater susceptibly to MS, while males have worse disease progression. These two characteristics of the disease are influenced by the immune system and the nervous system, respectively. Thus, sex differences in each system must be studied. Personalized medicine has been at the forefront of research recently, and studying sex differences in disease fits with this initiative. This review will discuss the known sex differences in MS and highlight how investigating them can lead to new insights and potential treatments for both men and women. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A systematic review about the epidemiology of primary progressive multiple sclerosis in Latin America and the Caribbean.

PubMed

Rojas, Juan Ignacio; Romano, Marina; Patrucco, Liliana; Cristiano, Edgardo

2018-02-24

Novel epidemiological data has appeared in recent years in Latin America (LATAM) regarding the epidemiology of multiple sclerosis (MS); however, most of this information is related to all MS subtypes, and no specific data was collected regarding the primary progressive form of MS (PPMS). The objective of this study was to perform an updated systematic review of the epidemiology of PPMS in LATAM. We conducted a systematic review of published epidemiological articles of PPMS from January 1997 to June 2017. No incidence data were found regarding PPMS. Differentiated prevalence was reported in 7 studies and ranged from 0.13 to 1.1 cases of PPMS per 100,000 inhabitants. Regarding subtype frequency, PPMS was observed in 10% of affected patients in proportional meta-analysis. No data about mortality were found. The study provides information on discriminated epidemiological features of PPMS in the region. The frequency observed was low in terms of prevalence. Follow up studies considering survival milestones and incidence data could provide a better understanding of the disease in the region. Copyright © 2018. Published by Elsevier B.V.

Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis.

PubMed

Shirani, Afsaneh; Zhao, Yinshan; Karim, Mohammad Ehsanul; Evans, Charity; Kingwell, Elaine; van der Kop, Mia L; Oger, Joel; Gustafson, Paul; Petkau, John; Tremlett, Helen

2012-07-18

Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

T Cells

MedlinePlus

... cells — have proven successful in treating animals with experimental allergic encephalomyelitis (EAE), an animal model of MS. Pilot clinical trials are in progress. Future experimental therapies may involve antibodies directed against the cytokines ...

Clinical outcomes following surgical management of coexistent cervical stenosis and multiple sclerosis: a cohort-controlled analysis.

PubMed

Lubelski, Daniel; Abdullah, Kalil G; Alvin, Matthew D; Wang, Timothy Y; Nowacki, Amy S; Steinmetz, Michael P; Ransohoff, Richard M; Benzel, Edward C; Mroz, Thomas E

2014-02-01

The presentation of myelopathy in patients with the concomitant diagnosis of cervical stenosis (CS) and multiple sclerosis (MS) complicates both diagnosis and treatment because of the similarities of presentation and disease progression. There are only a few published case series that examine this unique patient population. To define the demographic features and presenting symptoms of patients with both MS and CS and to investigate the immediate and long-term outcomes of surgery in patients with MS and CS. Matched cohort-controlled retrospective review of 77 surgical patients in the MS group and 77 surgical patients in the control group. Outcome measures were immediate and long-term postoperative neck pain, radiculopathy, and myelopathy; Nurick Disability and modified Japanese Orthopaedic Association scores were collected as well. Retrospective review was performed for all patients presenting at one institution between January 1996 and July 2011 with coexisting diagnoses of MS and CS who had presenting symptoms of myelopathy and who then underwent cervical decompression surgery. Each study patient was individually matched to a control patient of the same gender and age that did not have MS, but that did have cervical spondylotic myelopathy or myeloradiculopathy. Each control patient underwent the same surgical procedure within the same year. A total of 154 patients were reviewed, including 77 MS patients and 77 control patients, for an average follow-up of 58 months and 49 months, respectively. Patients in the control group were more likely to have preoperative neck pain (78% vs. 47%; p=.0001) and preoperative radiculopathy (90% vs. 75%; p=.03) than their counterparts in the MS group. Patients in the MS group had a significantly lower rate of postoperative resolution of myelopathic symptoms in both the short-term (39% in the MS group did not improve vs. 23% in the control group; p=.04) and the long-term (44% in the MS group did not improve vs. 19% in the control group; p=.004). Preoperative myelopathy scores were worse for the MS cohort as compared with the control cohort (1.8 vs. 1.2 in the Nurick scale, p<.0001; 13.7 vs. 15.0 in the modified Japanese Orthopaedic Association scale, p=.002). This difference in scores became even greater at the last follow-up visit with Nurick scores of 2.4 versus 0.9 (p<.0001) and modified Japanese Orthopaedic Association scores of 16.3 versus 12.4 (p<.0001) for the MS and control patients, respectively. Myelopathic patients with coexisting MS and CS improve after surgery, although at a lower rate and to a lesser degree than those without MS. Therefore, surgery should be considered for these patients. MS patients should be informed that myelopathy symptoms are less likely to be alleviated completely or may only be alleviated temporarily because of progression of MS and that surgery can help alleviate neck pain and radicular symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

MS 1512 cB58: A case study of star formation, metal enrichment and superwinds in Lyman break galaxies

NASA Astrophysics Data System (ADS)

Pettini, Max; Rix, Samantha A.; Steidel, Chuck C.; Hunt, Matthew P.; Shapley, Alice E.; Adelberger, Kurt L.

2002-07-01

Recent advances in instrumentation and observing techniques have made it possible to begin to study in detail the stellar populations and the interstellar media of galaxies at redshift z = 3, when the universe was still in its ‘teen years’. I illustrate recent progress in this field with the latest observations of the gravitationally lensed galaxy MS 1512- cB58.

M3MS-16OR0401086 – Report on NEAMS Workbench Support for MOOSE Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lefebvre, Robert A.; Langley, Brandon R.; Thompson, Adam B.

This report summarizes the status of the Nuclear Energy Advanced Modeling and Simulation (NEAMS) Workbench from Oak Ridge National Laboratory (ORNL) and the integration of the MOOSE framework. This report marks the completion of NEAMS milestone M3MS-16OR0401086. This report documents the developed infrastructure to support the MOOSE framework applications, the applications’ results, visualization status, the collaboration that facilitated this progress, and future considerations.

The importance of local criteria in the diagnosis of metabolic syndrome in Saudi Arabia

PubMed Central

Al Raddadi, Rajaa M.

2013-01-01

The clustering of risk factors predisposing an individual to cardiovascular morbidity and mortality are usually referred to as the ‘metabolic syndrome’ (MS). Several definitions exist, causing confusion to practicing clinicians. A consensus definition was reached by several major organizations stating that the presence of any three of five risk factors (abdominal obesity, elevated triglyceride, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose) constitutes a diagnosis. Cutoff points for each of the risk factors were defined, taking into account ethnicity in case of abdominal obesity. The prevalence of MS has been reported to be on the rise globally, and was mainly attributed to changes in diet and lifestyle, in addition to genetic factors and metabolic susceptibility. The risk of cardiovascular disease (CVD) has almost doubled and the risk of developing type 2 diabetes mellitus (T2DM) has increased fivefold in individuals diagnosed with MS. The prevalence T2DM in Saudi Arabia is increasing, making it an epidemic health hazard. Intervention programs to decrease the risk of progression from MS to full T2DM, and later CVD have been successful in many countries. Therefore, diagnosing MS is important to address risk factors and to prevent progression to the more serious chronic conditions. The prevalence of MS in Saudi adults varies from 16% to 40% depending on the definition used and the study location. Use of the consensus definition might decrease the number of missed cases. However, in the absence of local cutoff points for various risk factors for MS, the use of ratios such as waist/hip ratio and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, and family history of diabetes and CVD might aid diagnosis. Priority should be given to establishing national normal ranges, screening programs for hyperglycemia and hypertension, and community-directed programs to combat obesity and inactivity. PMID:23626902

Societal costs of multiple sclerosis in Ireland.

PubMed

Carney, Peter; O'Boyle, Derek; Larkin, Aidan; McGuigan, Christopher; O'Rourke, Killian

2018-05-01

This paper evaluates the impact of multiple sclerosis (MS) in Ireland, and estimates the associated direct, indirect, and intangible costs to society based on a large nationally representative sample. A questionnaire was developed to capture the demographics, disease characteristics, healthcare use, informal care, employment, and wellbeing. Referencing international studies, standardized survey instruments were included (e.g. CSRI, MFIS-5, EQ-5D) or adapted (EDSS) for inclusion in an online survey platform. Recruitment was directed at people with MS via the MS Society mailing list and social media platforms, as well as in traditional media. The economic costing was primarily conducted using a 'bottom-up' methodology, and national estimates were achieved using 'prevalence-based' extrapolation. A total of 594 people completed the survey in full. The sample had geographic, disease, and demographic characteristics indicating good representativeness. At an individual level, average societal cost was estimated at €47,683; the average annual costs for those with mild, moderate, and severe MS were calculated as €34,942, €57,857, and €100,554, respectively. For a total Irish MS population of 9,000, the total societal costs of MS amounted to €429m. Direct costs accounted for just 30% of the total societal costs, indirect costs amounted to 50% of the total, and intangible or QoL costs represented 20%. The societal cost associated with a relapse in the sample is estimated as €2,438. The findings highlight that up to 70% of the total costs associated with MS are not routinely counted. These "hidden" costs are higher in Ireland than the rest of Europe, due in part to significantly lower levels of workforce participation, a higher likelihood of permanent workforce withdrawal, and higher levels of informal care needs. The relationship between disease progression and costs emphasize the societal importance of managing and slowing the progression of the illness.

Metabolite profiling of a NIST Standard Reference Material for human plasma (SRM 1950): GC-MS, LC-MS, NMR, and clinical laboratory analyses, libraries, and web-based resources.

PubMed

Simón-Manso, Yamil; Lowenthal, Mark S; Kilpatrick, Lisa E; Sampson, Maureen L; Telu, Kelly H; Rudnick, Paul A; Mallard, W Gary; Bearden, Daniel W; Schock, Tracey B; Tchekhovskoi, Dmitrii V; Blonder, Niksa; Yan, Xinjian; Liang, Yuxue; Zheng, Yufang; Wallace, William E; Neta, Pedatsur; Phinney, Karen W; Remaley, Alan T; Stein, Stephen E

2013-12-17

Recent progress in metabolomics and the development of increasingly sensitive analytical techniques have renewed interest in global profiling, i.e., semiquantitative monitoring of all chemical constituents of biological fluids. In this work, we have performed global profiling of NIST SRM 1950, "Metabolites in Human Plasma", using GC-MS, LC-MS, and NMR. Metabolome coverage, difficulties, and reproducibility of the experiments on each platform are discussed. A total of 353 metabolites have been identified in this material. GC-MS provides 65 unique identifications, and most of the identifications from NMR overlap with the LC-MS identifications, except for some small sugars that are not directly found by LC-MS. Also, repeatability and intermediate precision analyses show that the SRM 1950 profiling is reproducible enough to consider this material as a good choice to distinguish between analytical and biological variability. Clinical laboratory data shows that most results are within the reference ranges for each assay. In-house computational tools have been developed or modified for MS data processing and interactive web display. All data and programs are freely available online at http://peptide.nist.gov/ and http://srmd.nist.gov/ .

[Revision of McDonald's new diagnostic criteria for multiple sclerosis].

PubMed

Wiendl, H; Kieseier, B C; Gold, R; Hohlfeld, R; Bendszus, M; Hartung, H-P

2006-10-01

In 2001, an international panel suggested new diagnostic criteria for multiple sclerosis (MS). These criteria integrate clinical, imaging (MRI), and paraclinical results in order to facilitate diagnosis. Since then, these so-called McDonald criteria have been broadly accepted and widely propagated. In the meantime a number of publications have dealt with the sensitivity and specificity for MS diagnosis and with implementing these new criteria in clinical practice. Based on these empirical values and newer data on MS, an international expert group recently proposed a revision of the criteria. Substantial changes affect (1) MRI criteria for the dissemination of lesions over time, (2) the role of spinal cord lesions in the MRI and (3) diagnosis of primary progressive MS. In this article we present recent experiences with the McDonald and revised criteria.

A new role for evoked potentials in MS? Repurposing evoked potentials as biomarkers for clinical trials in MS.

PubMed

Hardmeier, Martin; Leocani, Letizia; Fuhr, Peter

2017-09-01

Evoked potentials (EP) characterize signal conduction in selected tracts of the central nervous system in a quantifiable way. Since alteration of signal conduction is the main mechanism of symptoms and signs in multiple sclerosis (MS), multimodal EP may serve as a representative measure of the functional impairment in MS. Moreover, EP have been shown to be predictive for disease course, and thus might help to select patient groups at high risk of progression for clinical trials. EP can detect deterioration, as well as improvement of impulse propagation, independently from the mechanism causing the change. Therefore, they are candidates for biomarkers with application in clinical phase-II trials. Applicability of EP in multicenter trials has been limited by different standards of registration and assessment.

Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and its Application in Life Sciences

NASA Astrophysics Data System (ADS)

Xu, Gu-feng; Wang, Hong-mei

2001-08-01

Inductively-coupled plasma mass spectrometry (ICP-MS) has made much progress since its birth in the late 1990s. This paper will give a rather systematic overview on the use of this technique in new devices and technologies related to plasma source, sample-introducing device and detecting spectrometer etc. In this overview, an emphasis will be put on the evaluation of the ICP-MS technique in combination with a series of physical, chemical and biological techniques, such as laser ablation (LA), capillary electrophoresis (CE) and high performance liquid chromatograph (HPLC), along with their representative high accuracy and high sensitivity. Finally, comprehensive and fruitful applications of the ICP-MS and its combinative techniques in the detection of trace metallic elements and isotopes in complex biological and environmental samples will be revealed.

Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors.

PubMed

Thewissen, Kristof; Nuyts, Amber H; Deckx, Nathalie; Van Wijmeersch, Bart; Nagels, Guy; D'hooghe, Marie; Willekens, Barbara; Cras, Patrick; Eijnde, Bert O; Goossens, Herman; Van Tendeloo, Viggo F I; Stinissen, Piet; Berneman, Zwi N; Hellings, Niels; Cools, Nathalie

2014-04-01

The role of the adaptive immune system and more specifically T cells in the pathogenesis of multiple sclerosis (MS) has been studied extensively. Emerging evidence suggests that dendritic cells (DCs), which are innate immune cells, also contribute to MS. This study aimed to characterize circulating DC populations in MS and to investigate the contribution of MS-associated genetic risk factors to DCs. Ex vivo analysis of conventional (cDCs) and plasmacytoid DCs (pDCs) was carried out on peripheral blood of MS patients (n = 110) and age- and gender-matched healthy controls (n = 112). Circulating pDCs were significantly decreased in patients with chronic progressive MS compared to relapsing-remitting MS and healthy controls. While no differences in cDCs frequency were found between the different study groups, HLA-DRB1*1501(+) MS patients and patients not carrying the protective IL-7Rα haplotype 2 have reduced frequencies of circulating cDCs and pDCs, respectively. MS-derived DCs showed enhanced IL-12p70 production upon TLR ligation and had an increased expression of the migratory molecules CCR5 and CCR7 as well as an enhanced in vitro chemotaxis. DCs in MS are in a pro-inflammatory state, have a migratory phenotype and are affected by genetic risk factors, thereby contributing to pathogenic responses.

Dynamics and heterogeneity of brain damage in multiple sclerosis

PubMed Central

Martinez-Lapiscina, Elena H.; Andorra, Magi; Olsson, Tomas; Martin, Roland; Paul, Friedemann; Tegnér, Jesper

2017-01-01

Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale [EDSS] time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease. PMID:29073203

Dynamics and heterogeneity of brain damage in multiple sclerosis.

PubMed

Kotelnikova, Ekaterina; Kiani, Narsis A; Abad, Elena; Martinez-Lapiscina, Elena H; Andorra, Magi; Zubizarreta, Irati; Pulido-Valdeolivas, Irene; Pertsovskaya, Inna; Alexopoulos, Leonidas G; Olsson, Tomas; Martin, Roland; Paul, Friedemann; Tegnér, Jesper; Garcia-Ojalvo, Jordi; Villoslada, Pablo

2017-10-01

Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale [EDSS] time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease.

Severe impulsiveness as the primary manifestation of multiple sclerosis in a young female.

PubMed

Lopez-Meza, Elmer; Corona-Vazquez, Teresa; Ruano-Calderon, Luis A; Ramirez-Bermudez, Jesus

2005-12-01

Severe impulsiveness in the absence of apparent neurological signs has rarely been reported as a clinical presentation of multiple sclerosis (MS). An 11-year-old female developed progressive and sustained personality disturbances including disinhibition, hypersexuality, drug abuse, aggressiveness and suicide attempts, without neurological signs. She was given several unsuccessful psychopharmacological and psychotherapeutic interventions. At age 21, a diagnosis of MS was made, confirmed by imaging, laboratory and neurophysiological studies. Although unusual, MS may produce pure neurobehavioral disturbances. In the present case, widespread demyelinization produced a complex behavioral disorder, with features compatible with orbitofrontal and Klüver-Bucy syndromes.

Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study

PubMed Central

2011-01-01

Background Tissue Doppler imaging (TDI) is a noninvasive echocardiographic method for the diagnosis of diastolic dysfunction in patients with varying degrees of aortic stenosis (AS). Little is known however, on the utility of TDI in the serial assessment of diastolic abnormalities in AS. Objective The aim of the current proposal was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients enrolled in the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) study. Methods Conventional Doppler indices including peak early (E) and late (A) transmitral velocities, and E/A ratio were measured from spectral Doppler. Tissue Doppler measurements including early (E') and late (A') velocities of the lateral annulus were determined, and E/E' was calculated. Results The study population included 168 patients (56 ± 13 years), whose AS severity was categorized based on peak velocity at baseline (Group I: 2.5-3.0 m/s; Group II: 3.1-3.5 m/s; Group III: 3.6-4.0 m/s). Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were evaluated in all three groups. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin groups. In patients with increasing severity of AS in Groups I and II, the lateral E' was lower and the E/E' (as an estimate of increased left ventricular end-diastolic pressure) was higher at baseline (p < 0.05). However, treatment with rosuvastatin did not affect the progression of diastolic dysfunction from baseline to 3.5 year follow-up between patients in any of the three predefined groups. Conclusion In patients with mild to moderate asymptomatic AS, rosuvastatin did not attenuate the progression of diastolic dysfunction. PMID:21299902

Low levels of serum paraoxonase activities are characteristic of metabolic syndrome and may influence the metabolic-syndrome-related risk of coronary artery disease.

PubMed

Martinelli, Nicola; Micaglio, Roberta; Consoli, Letizia; Guarini, Patrizia; Grison, Elisa; Pizzolo, Francesca; Friso, Simonetta; Trabetti, Elisabetta; Pignatti, Pier Franco; Corrocher, Roberto; Olivieri, Oliviero; Girelli, Domenico

2012-01-01

Low concentrations of plasma high-density lipoprotein (HDLs) are characteristic in metabolic syndrome (MS). The antioxidant ability of HDLs is, at least in part, attributable to pleiotropic serum paraoxonase (PON1). Different PON1 activities have been assessed in 293 subjects with (n = 88) or without MS (n = 205) and with (n = 195) or without (n = 98) angiographically proven coronary artery disease (CAD). MS subjects had low PON1 activities, with a progressively decreasing trend by increasing the number of MS abnormalities. The activity versus 7-O-diethyl phosphoryl,3-cyano,4-methyl,7-hydroxycoumarin (DEPCyMC), which is considered a surrogate marker of PON1 concentration, showed the most significant association with MS, independently of both HDL and apolipoprotein A-I levels. Subjects with MS and low DEPCyMCase activity had the highest CAD risk (OR 4.34 with 95% CI 1.44-13.10), while no significant increase of risk was found among those with MS but high DEPCyMCase activity (OR 1.45 with 95% CI 0.47-4.46). Our results suggest that low PON1 concentrations are typical in MS and may modulate the MS-related risk of CAD.

Low Levels of Serum Paraoxonase Activities are Characteristic of Metabolic Syndrome and May Influence the Metabolic-Syndrome-Related Risk of Coronary Artery Disease

PubMed Central

Martinelli, Nicola; Micaglio, Roberta; Consoli, Letizia; Guarini, Patrizia; Grison, Elisa; Pizzolo, Francesca; Friso, Simonetta; Trabetti, Elisabetta; Pignatti, Pier Franco; Corrocher, Roberto; Olivieri, Oliviero; Girelli, Domenico

2012-01-01

Low concentrations of plasma high-density lipoprotein (HDLs) are characteristic in metabolic syndrome (MS). The antioxidant ability of HDLs is, at least in part, attributable to pleiotropic serum paraoxonase (PON1). Different PON1 activities have been assessed in 293 subjects with (n = 88) or without MS (n = 205) and with (n = 195) or without (n = 98) angiographically proven coronary artery disease (CAD). MS subjects had low PON1 activities, with a progressively decreasing trend by increasing the number of MS abnormalities. The activity versus 7-O-diethyl phosphoryl,3-cyano,4-methyl,7-hydroxycoumarin (DEPCyMC), which is considered a surrogate marker of PON1 concentration, showed the most significant association with MS, independently of both HDL and apolipoprotein A-I levels. Subjects with MS and low DEPCyMCase activity had the highest CAD risk (OR 4.34 with 95% CI 1.44–13.10), while no significant increase of risk was found among those with MS but high DEPCyMCase activity (OR 1.45 with 95% CI 0.47–4.46). Our results suggest that low PON1 concentrations are typical in MS and may modulate the MS-related risk of CAD. PMID:21960992

Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis.

PubMed

Jankovic, Slobodan M

2010-01-01

Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%-15%) or relapsing-remitting (85%-90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia, chills and depression. Efficacy of IFN-β1b in relapsing-remitting MS is higher than that of IFN-β1a, and similar to the efficacy of glatiramer acetate. These facts promote IFN-β1b as one of the most important drugs in the spectrum of immunological therapies for this debilitating disease.

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington's Disease: A Targeted GC-MS/MS Sterol Analysis.

PubMed

Kreilaus, Fabian; Spiro, Adena S; Hannan, Anthony J; Garner, Brett; Jenner, Andrew M

2015-01-01

Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. 24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.

Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma.

PubMed

Ellingson, B M; Sahebjam, S; Kim, H J; Pope, W B; Harris, R J; Woodworth, D C; Lai, A; Nghiemphu, P L; Mason, W P; Cloughesy, T F

2014-04-01

Pre-treatment ADC characteristics have been shown to predict response to bevacizumab in recurrent glioblastoma multiforme. However, no studies have examined whether ADC characteristics are specific to this particular treatment. The purpose of the current study was to determine whether ADC histogram analysis is a bevacizumab-specific or treatment-independent biomarker of treatment response in recurrent glioblastoma multiforme. Eighty-nine bevacizumab-treated and 43 chemotherapy-treated recurrent glioblastoma multiformes never exposed to bevacizumab were included in this study. In all patients, ADC values in contrast-enhancing ROIs from MR imaging examinations performed at the time of recurrence, immediately before commencement of treatment for recurrence, were extracted and the resulting histogram was fitted to a mixed model with a double Gaussian distribution. Mean ADC in the lower Gaussian curve was used as the primary biomarker of interest. The Cox proportional hazards model and log-rank tests were used for survival analysis. Cox multivariate regression analysis accounting for the interaction between bevacizumab- and non-bevacizumab-treated patients suggested that the ability of the lower Gaussian curve to predict survival is dependent on treatment (progression-free survival, P = .045; overall survival, P = .003). Patients with bevacizumab-treated recurrent glioblastoma multiforme with a pretreatment lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with bevacizumab-treated patients with a lower Gaussian curve < 1.2 μm(2)/ms. No differences in progression-free survival or overall survival were observed in the chemotherapy-treated cohort. Bevacizumab-treated patients with a mean lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with chemotherapy-treated patients. The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 μm(2)/ms have a survival advantage when treated with bevacizumab.

Increased tissue damage and lesion volumes in African Americans with multiple sclerosis.

PubMed

Weinstock-Guttman, B; Ramanathan, M; Hashmi, K; Abdelrahman, N; Hojnacki, D; Dwyer, M G; Hussein, S; Bergsland, N; Munschauer, F E; Zivadinov, R

2010-02-16

African American (AA) patients with multiple sclerosis (MS) have more rapid disease progression and poorer responses to disease-modifying therapies than white American (WA) patients with MS. To investigate brain MRI characteristics in AA compared to WA in a cohort of consecutive patients with MS. We studied 567 patients with MS (age: 45.1 +/- SD 9.8 years, disease duration: 13.4 +/- 8.6 years), comprised of 488 WA and 79 AA. All patients obtained clinical and quantitative MRI evaluation. The majority of patients, 96% of AA and 94% of WA, were on disease-modifying therapies. The MRI measures included T1-, T2-, and gadolinium contrast-enhancing (CE) lesion volumes (LV) and CE number, global and tissue-specific brain atrophy, and magnetization transfer ratio (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The associations between race and clinical and MRI measurements were assessed in regression analysis. The MTR values in lesions and in NAGM and NAWM were significantly lower in AA compared to WA. The AA group had 31% greater T2-LV and 101% greater T1-LV compared to WA. The MS Severity Score for AA (mean +/- SD = 4.3 +/- 2.9) was greater than for WA (3.8 +/- 2.5), despite a shorter disease duration in AA, indicating more aggressive clinical disease. African American patients showed increased tissue damage, as measured by magnetization transfer ratio, and presented higher lesion volumes compared to white Americans. The greater tissue damage and faster lesion volume accumulation may explain the rapid clinical progression in African American patients.

Arterial stiffness is an independent predictor for albuminuria progression among Asians with type 2 diabetes-A prospective cohort study.

PubMed

Zhang, Xiao; Low, Serena; Sum, Chee Fang; Tavintharan, Subramaniam; Yeoh, Lee Ying; Liu, Jianjun; Li, Na; Ang, Keven; Lee, Simon Bm; Tang, Wern Ee; Lim, Su Chi

2017-06-01

Albuminuria progression has been associated with renal deterioration in type 2 diabetes (T2DM). Central arterial stiffness can aggravate systemic vasculopathy by propagating elevated systolic and pulse pressures forward, thereby accentuating global vascular injury. We aim to investigate whether central arterial stiffness is an independent predictor for albuminuria progression in a multi-ethnic T2DM Asian cohort in Singapore. In a prospective cohort, 1012 T2DM patients were assessed at baseline and after a median follow-up of 3.1years. 880 patients with baseline normo- (urinary albumin-to-creatinine ratio (ACR)<30mg/g, n=579) and microalbuminuria (ACR=30-299mg/g, n=301) were divided into progression and non-progression groups according to ACR changes. Progression was defined as transition from normo- to microalbuminuria, micro- to macroalbuminuria, or normo- to macroalbuminuria. Central arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV) using applanation tonometry method. Stepwise multiple regression analysis was used to determine the predictor(s) for albuminuria progression. Albuminuria progression occurred in 178 patients (20.2%). Baseline PWV was higher in progression (10.1±2.9m/s) than non-progression group (9.2±2.4m/s, p<0.001). 1-SD increase in baseline PWV was associated with albuminuria progression (OR=1.457, 95% CI, 1.236-1.718, p<0.001). Stepwise regression analysis identified that baseline PWV (OR=1.241, 95% CI, 1.033-1.490, p=0.021), BMI (OR=1.046, 95% CI, 1.012-1.080, p=0.008), nature log-transformed estimated glomerular filtration rate (LneGFR) (OR=0.320, 95% CI, 0.192-0.530, p=0.010) and LnACR (OR=1.344, 95% CI, 1.187-1.522, p=0.008) are predictors for albuminuria progression. Increased central arterial stiffness at baseline predicted future progression of albuminuria. Our results suggest the potential benefit of ameliorating central arterial stiffness to retard albuminuria progression in T2DM. Copyright © 2017 Elsevier Inc. All rights reserved.

Information processing speed and attention in multiple sclerosis: Reconsidering the Attention Network Test (ANT).

PubMed

Roth, Alexandra K; Denney, Douglas R; Lynch, Sharon G

2015-01-01

The Attention Network Test (ANT) assesses attention in terms of discrepancies between response times to items that differ in the burden they place on some facet of attention. However, simple arithmetic difference scores commonly used to capture these discrepancies fail to provide adequate control for information processing speed, leading to distorted findings when patient and control groups differ markedly in the speed with which they process and respond to stimulus information. This study examined attention networks in patients with multiple sclerosis (MS) using simple difference scores, proportional scores, and residualized scores that control for processing speed through statistical regression. Patients with relapsing-remitting (N = 20) or secondary progressive (N = 20) MS and healthy controls (N = 40) of similar age, education, and gender completed the ANT. Substantial differences between patients and controls were found on all measures of processing speed. Patients exhibited difficulties in the executive control network, but only when difference scores were considered. When deficits in information processing speed were adequately controlled using proportional or residualized score, deficits in the alerting network emerged. The effect sizes for these deficits were notably smaller than those for overall information processing speed and were also limited to patients with secondary progressive MS. Deficits in processing speed are more prominent in MS than those involving attention, and when the former are properly accounted for, differences in the latter are confined to the alerting network.

Comparison of qualitative and quantitative analysis of T2-weighted MRI scans in chronic-progressive multiple sclerosis

NASA Astrophysics Data System (ADS)

Adams, Hans-Peter; Wagner, Simone; Koziol, James A.

1998-06-01

Magnetic resonance imaging (MRI) is routinely used for the diagnosis of multiple sclerosis (MS), and for objective assessment of the extent of disease as a marker of treatment efficacy in MS clinical trials. The purpose of this study is to compare the evaluation of T2-weighted MRI scans in MS patients using a semi-automated quantitative technique with an independent assessment by a neurologist. Baseline, 6- month, and 12-month T2-weighted MRI scans from 41 chronic progressive MS patients were examined. The lesion volume ranged from 0.50 to 51.56 cm2 (mean: 8.08 cm2). Reproducibility of the quantitative technique was assessed by the re-evaluation of a random subset of 20 scans, the coefficient of variation of the replicate determinations was 8.2%. The reproducibility of the neurologist evaluations was assessed by the re-evaluation of a random subset of 10 patients. The rank correlation between the results of the two methods was 0.097, which did not significantly differ from zero. Disease-related activity in T2-weighted MRI scans is a multi-dimensional construct, and is not adequately summarized solely by determination of lesion volume. In this setting, image analysis software should not only support storage and retrieval as sets of pixels, but should also support links to an anatomical dictionary.

The Proteomic Analysis of Pancreatic Exocrine Insufficiency Protein Marker in Type 2 Diabetes Mellitus Patients

NASA Astrophysics Data System (ADS)

Srihardyastutie, Arie; Soeatmadji, DW; Fatchiyah; Aulanni'am

2018-01-01

Type 2 Diabetes Mellitus (T2D) is the vast majority case of diabetes. Patient with T2D is at higher risk for developing acute or chronic pancreatitis. Prolonged hyperglycemia results in damages to tissue, which also causes dysfunctions of some organ systems, including enzyme or hormone secretions. Commonly, dysfunction or insufficiency of pancreatic exocrine is evaluated by increasing activity of serum pancreatic enzyme, such as amylase and lipase. Although incidence of pancreatitis was found in Indonesian T2D, the pathogenic mechanism still unclear. The aim of this study was to characterize the marker protein that indicated the correlation of pancreatic exocrine insufficiency with progression of T2D. Proteomic analysis using LC-MS/MS was used in identification and characterization of protein marker which indicates insufficiency pancreatic exocrine. First step, protein profile was analyzed by SDS-PAGE methods using serum sample of T2D compared with normal or healthy control, as negative control, and pancreatitis patients, as positive control. Protein with 18 kDa was found as a candidate protein marker which indicated the pancreatic exocrine insufficiency in T2D. The further identification of that protein using LC-MS/MS showed 4 peptide fragments. In silico analysis of the peptide fragment indicated the correlation of pancreatic exocrine insufficiency with progression of T2D was METTL10 - methyltransferase like protein-10.

Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

PubMed

Conte, Antonella; Bettolo, Chiara Marini; Onesti, Emanuela; Frasca, Vittorio; Iacovelli, Elisa; Gilio, Francesca; Giacomelli, Elena; Gabriele, Maria; Aragona, Massimiliano; Tomassini, Valentina; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio

2009-05-01

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

Infection risk in patients on multiple sclerosis therapeutics.

PubMed

Williamson, Eric M; Berger, Joseph R

2015-03-01

The interface of multiple sclerosis (MS) and infection occurs on several levels. First, infectious disease has been postulated as a potential trigger, if not cause, of MS. Second, exacerbation of MS has been well-documented as a consequence of infection, and, lastly, infectious diseases have been recognized as a complication of the therapies currently employed in the treatment of MS. MS is a disease in which immune dysregulation is a key component. Examination of central nervous system (CNS) tissue of people affected by MS demonstrates immune cell infiltration, activation and inflammation. Therapies that alter the immune response have demonstrated efficacy in reducing relapse rates and evidence of brain inflammation on magnetic resonance imaging (MRI). Despite the altered immune response in MS, there is a lack of evidence that these patients are at increased risk of infectious disease in the absence of treatment or debility. Links between infections and disease-modifying therapies (DMTs) used in MS will be discussed in this review, as well as estimates of occurrence and ways to potentially minimize these risks. We address infection in MS in a comprehensive fashion, including (1) the impact of infections on relapse rates in patients with MS; (2) a review of available infection data from pivotal trials and postmarketing studies for the approved and experimental DMTs, including frequency, types and severity of infections; and (3) relevant risk minimization strategies, particularly as they pertain to progressive multifocal leukoencephalopathy (PML).

A 52-year-old woman with disabling peripheral neuropathy: review of diabetic polyneuropathy.

PubMed

Rutkove, Seward B

2009-10-07

Ms Q is a 52-year-old woman who has had progressive polyneuropathy in the setting of diabetes for the past 8 years. Ms Q's major disability is that of increasingly severe neuropathic pain and cramps that have been poorly responsive to a variety of therapies, including gabapentin and topiramate. The diagnosis of and differential diagnosis for diabetic polyneuropathy are reviewed herein. In general, treatment options for diabetic polyneuropathy remain primarily symptomatic. Improving the metabolic profile through weight loss, exercise, and if necessary, medications may help slow neuropathy progression. Many medications are effective in reducing pain, and newly developed ones, such as pregabalin and duloxetine, while specifically marketed for diabetic neuropathy, are likely to be no better and are considerably more expensive than older ones. Alpha-lipoic acid appears to be effective as well.

Heart rate variability in idiopathic dilated cardiomyopathy: relation to disease severity and prognosis.

PubMed Central

Yi, G.; Goldman, J. H.; Keeling, P. J.; Reardon, M.; McKenna, W. J.; Malik, M.

1997-01-01

OBJECTIVE: To assess the clinical importance of heart rate variability (HRV) in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS AND METHODS: Time domain analysis of 24 hour HRV was performed in 64 patients with DCM, 19 of their relatives with left ventricular enlargement (possible early DCM), and 33 healthy control subjects. RESULTS: Measures of HRV were reduced in patients with DCM compared with controls (P < 0.05). HRV parameters were similar in relatives and controls. Measures of HRV were lower in DCM patients in whom progressive heart failure developed (n = 28) than in those who remained clinically stable (n = 36) during a follow up of 24 (20) months (P = 0.0001). Reduced HRV was associated with NYHA functional class, left ventricular end diastolic dimension, reduced left ventricular ejection fraction, and peak exercise oxygen consumption (P < 0.05) in all patients. DCM patients with standard deviation of normal to normal RR intervals calculated over the 24 hour period (SDNN) < 50 ms had a significantly lower survival rate free of progressive heart failure than those with SDNN > 50 ms (P = 0.0002, at 12 months; P = 0.0001, during overall follow up). Stepwise multiple regression analysis showed that SDNN < 50 ms identified, independently of other clinical variables, patients who were at increased risk of developing progressive heart failure (P = 0.0004). CONCLUSIONS: HRV is reduced in patients with DCM and related to disease severity. HRV is clinically useful as an early non-invasive marker of DCM deterioration. PMID:9068391

Dietary interventions for multiple sclerosis.

PubMed

Farinotti, Mariangela; Vacchi, Laura; Simi, Silvana; Di Pietrantonj, Carlo; Brait, Lorenzo; Filippini, Graziella

2012-12-12

Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids (PUFAs) and vitamins, might improve outcomes in people with multiple sclerosis (MS). Diets and dietary supplements are much used by people with MS in the belief that they might improve disease outcomes and overcome the effectiveness limits of conventional treatments.This is an update of the Cochrane review "Dietary intervention for multiple sclerosis" (first published on The Cochrane Library 2007, Issue 1). To answer MS patients' questions regarding the efficacy and safety of dietary regimens for MS. Can changes in dietary habits be an effective intervention for MS patients? Are the potential side effects of these interventions known, and have they been measured? Are potential interactions between dietary interventions and other curative or symptomatic treatments known and have they been studied? We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (November 2011), CENTRAL (The Cochrane Library 2011, Issue 4), MEDLINE (PubMed) (1966 to November 2011), EMBASE (embase.com) (1974 to November 2011) and reference lists of papers found. All controlled trials (randomised controlled trials (RCTs) and controlled clinical trials (CCTs)) on a specific dietary intervention, diet plan or dietary supplementation, except for vitamin D supplementation, compared to no dietary modification or placebo were eligible. Two review authors independently selected articles, assessed trial quality and extracted data. Data were entered and analysed in RevMan.Dichotomous data were summarised as relative risks (RR) with 95% confidence intervals (95% CI) using a random-effects model in the presence of heterogeneity (I² > 60%). Continuous data were analysed using weighted mean differences, determined by the difference between the pre- and post-intervention changes in the treatment and control groups. Six RCTs that investigated PUFAs emerged from the search strategy, accounting for 794 randomised patients.PUFAs did not have a significant effect on disease progression at 24 months. Omega-6 fatty acids (11 to 23 g/day linoleic acid) didn't show any benefit in 144 MS patients (RR 1.04, 95% CI 0.66 to 1.63). Linoleic acid (2.9 to 3.4 g/day) had no benefit in 65 chronic progressive MS patients (RR 0.78, 95% CI 0.43 to 1.42). Omega-3 fatty acids had no benefit in 292 relapsing remitting MS patients (RR 0.82, 95% CI 0.65 to 1.03, P = 0.08).Slight potential benefits in relapse outcomes were associated with omega-6 fatty acids in some studies, however these findings were limited by the reduced validity of the endpoints. No judgements about safety or patient-reported outcomes were possible. In general, trial quality was poor.No studies on vitamin supplementation and allergen-free diets were analysed as none met the eligibility criteria, mainly due to lack of clinical outcomes. PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), but they may tend to reduce the frequency of relapses over two years. However, the data that are available are insufficient to assess a real benefit or harm from PUFA supplementation because of their uncertain quality.Evidence on the possible benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking. More research is required to assess the effectiveness of dietary interventions in MS.

Identifying cancer biomarkers by mass spectrometry-based glycomics

PubMed Central

Mechref, Yehia; Hu, Yunli; Garcia, Aldo; Hussein, Ahmed

2013-01-01

Correlations between aberrant glycosylation and cancer have been established for decades. The major advances in mass spectrometry (MS) and separation science have rapidly advanced detailed characterization of the changes associated with cancer development and progression. Over the past 10 years, many reports have described MS-based glycomic methods directed toward comparing the glycomic profiles of different human specimens collected from disease-free individuals and patients with cancers. Glycomic profiling of glycoproteins isolated from human specimens originating from disease-free individuals and patients with cancers have also been performed. Profiling of native, labeled, and permethylated glycans has been acquired using MALDI-MS and LC-MS. This review focuses on describing, discussing, and evaluating the different glycomic methods employed to characterize and quantify glycomic changes associated with cancers of different organs, including breast, colon, esophagus, liver, ovarian, pancreas, and prostate. PMID:22740464

Nonconventional MRI biomarkers for in vivo monitoring of pathogenesis in multiple sclerosis.

PubMed

Londoño, Ana C; Mora, Carlos A

2014-12-01

To date, biomarkers based on nonconventional MRI have not been standardized for diagnosis and follow-up of patients with multiple sclerosis (MS). The sequential monitoring of pathogenesis in MS by imaging of the normal appearing brain tissue is an important research tool in understanding the early stages of MS. In this review, we focus on the importance of deciphering the physiopathogenesis of the disease cascade in vivo based on imaging biomarkers that allow a correlation with immunohistochemistry and molecular biology findings in order to provide earlier clinical diagnosis and better individualization of treatment and follow-up in patients with MS. Among the nonconventional imaging techniques available, we remark on the importance of proton magnetic resonance spectroscopy imaging because of its ability to assist in the simultaneous evaluation of different events in the pathogenesis of MS that cannot be determined by conventional MRI. Nonconventional MRI and the use of novel contrast agents are expected to elucidate the process of neuroinflammation and excitotoxicity in vivo that characterizes MS, thus leading to more specific neuroprotective and immunomodulatory therapies and reducing progression toward disability.

Advanced MRI in Multiple Sclerosis: Current Status and Future Challenges

PubMed Central

Fox, Robert J.; Beall, Erik; Bhattacharyya, Pallab; Chen, Jacqueline; Sakaie, Ken

2011-01-01

Synopsis Magnetic resonance imaging (MRI) has rapidly become a leading research tool in the study of multiple sclerosis (MS). Conventional imaging is useful in diagnosis and management of the inflammatory stages of MS, but has limitations in describing the degree of tissue injury as well as the cause of progressive disability seen in the later stages of disease. Advanced MRI techniques hold promise to fill this void. Magnetization transfer imaging is a widely available technique that can characterize demyelination and may be useful in measuring putative remyelinating therapies. Diffusion tensor imaging describes the three-dimensional diffusion of water and holds promise in characterizing neurodegeneration and putative neuroprotective therapies. Spectroscopy measures the imbalance of cellular metabolites and could help unravel the pathogenesis of neurodegeneration in MS. Functional (f) MRI can be used to understand the functional consequences of MS injury, including the impact on cortical function and compensatory mechanisms. These imaging tools hold great promise to increase our understanding of MS pathogenesis and provide greater insight into the efficacy of new MS therapies. PMID:21439446

Frequency of viral infections and environmental factors in multiple sclerosis.

PubMed

Eftekharian, Mohammad Mahdi; Ghannad, Masoud Sabouri; Taheri, Mohammad; Roshanaei, Ghodratollah; Mazdeh, Mehrdokht; Musavi, Mehrnoosh; Hormoz, Mona Bahmani

2016-06-08

Multiple sclerosis (MS) is a complicated disease which occurs due to relationship between genes and environmental factors that causes tissue damage by autoimmune mechanisms.We investigated and illustrated the hypotheses correlated to the evidence of several putative environmental risk factors for MS onset and progression in this part of Iran. Univariate logistic regression was used to detect the effects of environmental factors on the risk of MS. Data were analyzed using SPSS version 16. The childhood history of patients with rubella, measles and chickenpox increased the risk of MS significantly. Moreover, low consumption of dairy products, avoidance of seafood consumption, cigarette smoking and exposure to tobacco smoke, stress, anxiety disorders, depress and disturbing thoughts, negative and disturbing thoughts, developing a sudden shock upon hearing bad news, having obsessive-compulsive and being depressed increased the risk of MS significantly. The results of the current research partially solved the puzzling question of complex interplay between environmental factors and MS disease in this part of Iran. Incorporating these factors enables more powerful and accurate detection of novel risk factors with diagnostic and prognostic methods.

Mass spectrometric analysis of sulfur mustard-induced biomolecular adducts: Are DNA adducts suitable biomarkers of exposure?

PubMed

Zubel, Tabea; Bürkle, Alexander; Mangerich, Aswin

2018-09-01

The bi-functional chemical warfare agent sulfur mustard (SM), whose release in asymmetric conflicts or terrorist attacks represents a realistic threat, induces several kinds of biomolecular adducts, including highly toxic DNA adducts. Isotope dilution liquid chromatographic tandem mass spectrometry (ID-LC-MS/MS) is considered the gold standard for highly accurate, precise, specific and sensitive quantification of DNA adducts in general. Recently, a number of LC-MS/MS approaches have been established to analyze SM-induced protein and DNA adducts in cell culture and rodent animal models. As DNA adducts are mechanism-based biomarkers for SM exposure, results from such studies provide a deeper understanding of the etiology of SM-induced pathologies, especially of long-term effects such as cancer formation. As a result, medical treatment of SM-exposed individuals might be improved. Yet, despite the progress that has been made during the last years, there is still a need for advanced methods of ID-LC-MS/MS for the detection and quantitation of SM adducts. Copyright © 2017 Elsevier B.V. All rights reserved.

Increasing Physical Activity and Participation in People With Multiple Sclerosis: A Review.

PubMed

Backus, Deborah

2016-09-01

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) affecting >2.5 million people worldwide. Damage to neurons in the CNS causes various sensorimotor and cognitive symptoms, such as fatigue, pain, spasticity, memory deficits, and impairment of mobility. Until the late 1990s, it was believed that symptoms of MS would be worsened with physical exertion and people with MS were encouraged to limit physical activity and exertion. Not only has emerging evidence suggested that physical activity, including exercise, is safe for people with MS, there is also evidence that at least some of the disability that occurs after MS is due to secondary deconditioning from the sedentary lifestyle adopted because of the symptoms of MS, not just CNS damage alone. Therefore, not only is physical activity safe, it is also required for maintaining function and health in people with MS. The purpose of this article is to review the unique physical and social barriers to physical activity in people with MS, including those with moderate to severe disability who use a wheelchair or scooter for mobility. We will discuss how existing guidelines for physical activity may not meet the needs of people with MS and present evidence-based considerations for promoting physical activity in people with MS. Ultimately, the goal is to overcome the barriers to physical activity and improve health, participation, and quality of life in people with MS. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling

PubMed Central

Tambalo, Stefano; Peruzzotti-Jametti, Luca; Rigolio, Roberta; Fiorini, Silvia; Bontempi, Pietro; Mallucci, Giulia; Balzarotti, Beatrice; Marmiroli, Paola; Sbarbati, Andrea; Cavaletti, Guido

2015-01-01

Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS. PMID:26157006

Managing the oral side-effects of medications used to treat multiple sclerosis.

PubMed

Cockburn, N; Pateman, K; Taing, M W; Pradhan, A; Ford, P J

2017-09-01

Many medications used to manage multiple sclerosis (MS) affect oral health. This review aimed to identify the oral side-effects of the current drugs recommended in Australia to treat MS and make dental practitioners aware of the range of symptoms. The Australian Therapeutic Guidelines and the Australian Medicines Handbook were searched for medications used to treat MS. For each medication, the generic name, class, route of administration, dosage and drug company reported side-effects were extracted from the online Monthly Index of Medical Specialties (MIMs) database. Meyler's Side-effect of Drugs Encyclopaedia was used to identify any additional oral adverse reactions to medications used to treat MS. Fourteen drugs were identified for the treatment of MS progression and 13 drugs for the treatment of MS symptoms. For these medications, 18 oral side-effects were documented: xerostomia was the most common, followed by dysgeusia, dysphagia, mouth ulceration and sinusitis. Anticholinergic drugs caused xerostomia while immunosuppressants resulted in more infection-related side-effects. Dental practitioners should be aware of the range of symptoms likely to be reported by this population. Clinicians are encouraged to continue providing dental care for their patients who develop MS and refer complex cases to specialists. © 2017 Australian Dental Association.

[Cormorbidity in multiple sclerosis and its therapeutic approach].

PubMed

Estruch, Bonaventura Casanova

2014-12-01

Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Salate derivatives found in sunscreens block experimental autoimmune encephalomyelitis in mice

PubMed Central

Wang, Yanping; Marling, Steven J.; Plum, Lori A.; DeLuca, Hector F.

2017-01-01

UV light suppresses experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, in mice and may be responsible for the decreased incidence of MS in equatorial regions. To test this concept further, we applied commercially available sunblock preparations to mice before exposing them to UV radiation. Surprisingly, some of the sunblock preparations blocked EAE without UV radiation. Furthermore, various sunblock preparations had variable ability to suppress EAE. By examining the components of the most effective agents, we identified homosalate and octisalate as the components responsible for suppressing EAE. Thus, salates may be useful in stopping the progression of MS, and may provide new insight into mechanisms of controlling autoimmune disease. PMID:28739922

Performance Evaluation of the Q Exactive HF-X for Shotgun Proteomics.

PubMed

Kelstrup, Christian D; Bekker-Jensen, Dorte B; Arrey, Tabiwang N; Hogrebe, Alexander; Harder, Alexander; Olsen, Jesper V

2018-01-05

Progress in proteomics is mainly driven by advances in mass spectrometric (MS) technologies. Here we benchmarked the performance of the latest MS instrument in the benchtop Orbitrap series, the Q Exactive HF-X, against its predecessor for proteomics applications. A new peak-picking algorithm, a brighter ion source, and optimized ion transfers enable productive MS/MS acquisition above 40 Hz at 7500 resolution. The hardware and software improvements collectively resulted in improved peptide and protein identifications across all comparable conditions, with an increase of up to 50 percent at short LC-MS gradients, yielding identification rates of more than 1000 unique peptides per minute. Alternatively, the Q Exactive HF-X is capable of achieving the same proteome coverage as its predecessor in approximately half the gradient time or at 10-fold lower sample loads. The Q Exactive HF-X also enables rapid phosphoproteomics with routine analysis of more than 5000 phosphopeptides with short single-shot 15 min LC-MS/MS measurements, or 16 700 phosphopeptides quantified across ten conditions in six gradient hours using TMT10-plex and offline peptide fractionation. Finally, exciting perspectives for data-independent acquisition are highlighted with reproducible identification of 55 000 unique peptides covering 5900 proteins in half an hour of MS analysis.

The Role of the Gut Microbiome in Multiple Sclerosis Risk and Progression: Towards Characterization of the "MS Microbiome".

PubMed

Pröbstel, Anne-Katrin; Baranzini, Sergio E

2018-01-01

Multiple sclerosis (MS) is the prototypic complex disease, in which both genes and the environment contribute to its pathogenesis. To date, > 200 independent loci across the genome have been associated with MS risk. However, these only explain a fraction of the total phenotypic variance, suggesting the possible presence of additional genetic factors, and, most likely, also environmental factors. New DNA sequencing technologies have enabled the sequencing of all kinds of microorganisms, including those living in and around humans (i.e., microbiomes). The study of bacterial populations inhabiting the gut is of particular interest in autoimmune diseases owing to their key role in shaping immune responses. In this review, we address the potential crosstalk between B cells and the gut microbiota, a relevant scenario in light of recently approved anti-B-cell therapies for MS. In addition, we review recent efforts to characterize the gut microbiome in patients with MS and discuss potential challenges and future opportunities. Finally, we describe the international MS microbiome study, a multicenter effort to study a large population of patients with MS and their healthy household partners to define the core MS microbiome, how it is shaped by disease-modifying therapies, and to explore potential therapeutic interventions.

Epstein-Barr virus and multiple sclerosis.

PubMed

Lucas, R M; Hughes, A M; Lay, M-L J; Ponsonby, A-L; Dwyer, D E; Taylor, B V; Pender, M P

2011-10-01

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.

A Century of Progress in Molecular Mass Spectrometry

NASA Astrophysics Data System (ADS)

McLafferty, Fred W.

2011-07-01

The first mass spectrum of a molecule was measured by J.J. Thomson in 1910. Mass spectrometry (MS) soon became crucial to the study of isotopes and atomic weights and to the development of atomic weapons for World War II. Its notable applications to molecules began with the quantitative analysis of light hydrocarbons during World War II. When I joined the Dow Chemical Company in 1950, MS was not favored by organic chemists. This situation improved only with an increased understanding of gaseous ion chemistry, which was obtained through the use of extensive reference data. Gas chromatography-MS was developed in 1956, and tandem MS was first used a decade later. In neutralization-reionization MS, an unusual, unstable species is prepared by ion-beam neutralization and characterized by reionization. Electrospray ionization of a protein mixture produces its corresponding ionized molecules. In top-down proteomics, ions from an individual component can be mass separated and subjected to collision-activated and electron-capture dissociation to provide extensive sequence information.

A rare presentation of atypical demyelination: tumefactive multiple sclerosis causing Gerstmann’s syndrome

PubMed Central

2014-01-01

Background Tumefactive demyelinating lesions are a rare manifestation of multiple sclerosis (MS). Differential diagnosis of such space occupying lesions may not be straightforward and sometimes necessitate brain biopsy. Impaired cognition is the second most common clinical manifestation of tumefactive MS; however complex cognitive syndromes are unusual. Case presentation We report the case of a 30 year old woman who presented with Gerstmann’s syndrome. MRI revealed a large heterogeneous contrast enhancing lesion in the left cerebral hemisphere. Intravenous corticosteroids did not stop disease progression. A tumour or cerebral lymphoma was suspected, however brain biopsy confirmed inflammatory demyelination. Following diagnosis of tumefactive MS treatment with natalizumab effectively suppressed disease activity. Conclusions The case highlights the need for clinicians, radiologists and surgeons to appreciate the heterogeneous presentation of tumefactive MS. Early brain biopsy facilitates rapid diagnosis and management. Treatment with natalizumab may be useful in cases of tumefactive demyelination where additional evidence supports a diagnosis of relapsing MS. PMID:24694183

G protein-coupled receptors as therapeutic targets for multiple sclerosis

PubMed Central

Du, Changsheng; Xie, Xin

2012-01-01

G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future. PMID:22664908

Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.

PubMed

Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2014-05-01

The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; p<0.05) only in the progressive group. In the relapsing patients there was an inverse correlation between PKBPND and BH total lesion volume in whole brain (r=-0.781; p<0.05). When progressive patients were grouped according to the disability outcome at 2years from the PK-PET scan, the total PKBPND in BHs was found to be a significant outcome predictor of disability (p<0.01). Our findings show that relapsing and progressive patients have heterogeneous patterns of PKBPND in T1 BHs and indicate that BHs are not just "holes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Application of Item Response Theory to Modeling of Expanded Disability Status Scale in Multiple Sclerosis.

PubMed

Novakovic, A M; Krekels, E H J; Munafo, A; Ueckert, S; Karlsson, M O

2017-01-01

In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease.

PubMed

Mykicki, Nadine; Herrmann, Alexander M; Schwab, Nicholas; Deenen, René; Sparwasser, Tim; Limmer, Andreas; Wachsmuth, Lydia; Klotz, Luisa; Köhrer, Karl; Faber, Cornelius; Wiendl, Heinz; Luger, Thomas A; Meuth, Sven G; Loser, Karin

2016-10-26

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (T H 1) and T H 17 cells cause demyelination and neuronal degeneration. Regulatory T cells (T reg ) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, T reg function is impaired. We show that a recently approved drug, Nle 4 -d-Phe 7 -α-melanocyte-stimulating hormone (NDP-MSH), induced functional T reg , resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders. Copyright © 2016, American Association for the Advancement of Science.

Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

PubMed Central

Kuenz, Bettina; Lutterotti, Andreas; Ehling, Rainer; Gneiss, Claudia; Haemmerle, Monika; Rainer, Carolyn; Deisenhammer, Florian; Schocke, Michael; Berger, Thomas; Reindl, Markus

2008-01-01

Background There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138−) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13. Conclusions Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS. PMID:18596942

Identification and characterization of proteins isolated from microvesicles derived from human lung cancer pleural effusions.

PubMed

Park, Jung Ok; Choi, Do-Young; Choi, Dong-Sic; Kim, Hee Joung; Kang, Jeong Won; Jung, Jae Hun; Lee, Jeong Hwa; Kim, Jayoung; Freeman, Michael R; Lee, Kye Young; Gho, Yong Song; Kim, Kwang Pyo

2013-07-01

Microvesicles (MVs, also known as exosomes, ectosomes, microparticles) are released by various cancer cells, including lung, colorectal, and prostate carcinoma cells. MVs released from tumor cells and other sources accumulate in the circulation and in pleural effusion. Although recent studies have shown that MVs play multiple roles in tumor progression, the potential pathological roles of MV in pleural effusion, and their protein composition, are still unknown. In this study, we report the first global proteomic analysis of highly purified MVs derived from human nonsmall cell lung cancer (NSCLC) pleural effusion. Using nano-LC-MS/MS following 1D SDS-PAGE separation, we identified a total of 912 MV proteins with high confidence. Three independent experiments on three patients showed that MV proteins from PE were distinct from MV obtained from other malignancies. Bioinformatics analyses of the MS data identified pathologically relevant proteins and potential diagnostic makers for NSCLC, including lung-enriched surface antigens and proteins related to epidermal growth factor receptor signaling. These findings provide new insight into the diverse functions of MVs in cancer progression and will aid in the development of novel diagnostic tools for NSCLC. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis.

PubMed

Madeddu, Roberto; Farace, Cristiano; Tolu, Paola; Solinas, Giuliana; Asara, Yolande; Sotgiu, Maria Alessandra; Delogu, Lucia Gemma; Prados, Jose Carlos; Sotgiu, Stefano; Montella, Andrea

2013-02-01

The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and β-tubulin (β-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and β-Tub II proteins were significantly higher (p < 0.0001) in MS than in OND group; no significant difference (p > 0.05) was found between MS and OND with regard to β-Tub III. Interestingly, levels of β-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of β-Tub II and GFAP were found in remitting MS forms. However, with the exception of β-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate β-Tub II as a potential candidate for diagnostic and β-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.

Multiple Sclerosis impact on employment and income in New Zealand.

PubMed

Pearson, J F; Alla, S; Clarke, G; Mason, D F; Anderson, T; Richardson, A; Miller, D H; Sabel, C E; Abernethy, D A; Willoughby, E W; Taylor, B V

2017-09-01

We investigated the demographic, social and clinical characteristics associated with employment status and income for people with multiple sclerosis (MS) in New Zealand (NZ). The NZ National MS Prevalence study included all persons resident in NZ on census day 2006 diagnosed with MS (96.7% coverage). Factors associated with employment and income status among the working age population (25-64 years) were identified by linear regression. Over 90% of working age people with MS (n=1727) had a work history, but 54% were not working. Work loss occurred early in the disease course, and at low disability (P<.001). Advancing age, progressive disease, longer disease duration, higher disability levels, partner loss and lower education were associated with work loss (P<.001). Working age people with MS had lower income than the NZ population (P<.0001). Higher qualifications yielded no additional income for MS females and about half the additional income for MS males (P<.0001). MS profoundly reduces employment and income early in the disease course, and at low levels of disability, however, unemployment is not entirely accounted for by clinical, social and demographic factors. These findings suggest social supports should be explored early in the disease course to reduce loss of income and unemployment for people with MS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Biomechanical and injury response to posterolateral loading from torso side airbags.

PubMed

Hallman, Jason J; Yoganandan, Narayan; Pintar, Frank A

2010-11-01

This study characterized thoracoabdominal response to posterolateral loading from a seat-mounted side airbag. Seven unembalmed post-mortem human subjects were exposed to ten airbag deployments. Subjects were positioned such that the deploying airbag first contacted the posterolateral thorax between T6 and L1 while stationary (n = 3 x 2 aspects) or while subjected to left lateral sled impact at ΔV = 6.7 m/s (n = 4). Chestband contours were analyzed to quantify deformation direction in the thoracic x-y plane (zero degrees indicating anterior and 180° indicating posterior), magnitude, rate, and viscous response. Skeletal injuries were consistent with posterolateral contact; visceral injuries consisted of renal (n = 1) or splenic (n = 3) lacerations. Deformation direction was transient during sled impact, progressing from 122 ± 5° at deformation onset to 90° following maximum deflection. Angles from stationary subjects progressed from 141 ± 9° to 120°. Peak normalized deflections, peak rates, and VCmax ranges were 0.075 - 0.171, 3.7 - 12.7 m/s, and 0.3 - 0.6 m/s with stationary airbag, respectively; ranges were 0.167 - 0.297, 7.4 - 18.3 m/s, and 0.7 - 3.0 m/s with airbag sled impact, respectively. Peak deflections were measured at angles between 99° - 135° and 98° - 125° for stationary and dynamic conditions, respectively. Because of deflection angle transience and localized injury response, both posterolateral and lateral injury metrics may be required for this boundary condition. Contrasted with flat rigid or anterolateral loading, biomechanical response to side airbag interaction may be augmented by peak normalized deflection or VCmax at 130°.

Biomechanical and Injury Response to Posterolateral Loading from Torso Side Airbags

PubMed Central

Hallman, Jason J.; Yoganandan, Narayan; Pintar, Frank A.

2013-01-01

This study characterized thoracoabdominal response to posterolateral loading from a seat-mounted side airbag. Seven unembalmed post-mortem human subjects were exposed to ten airbag deployments. Subjects were positioned such that the deploying airbag first contacted the posterolateral thorax between T6 and L1 while stationary (n = 3 × 2 aspects) or while subjected to left lateral sled impact at ΔV = 6.7 m/s (n = 4). Chestband contours were analyzed to quantify deformation direction in the thoracic x–y plane (zero degrees indicating anterior and 180° indicating posterior), magnitude, rate, and viscous response. Skeletal injuries were consistent with posterolateral contact; visceral injuries consisted of renal (n = 1) or splenic (n = 3) lacerations. Deformation direction was transient during sled impact, progressing from 122 ± 5° at deformation onset to 90° following maximum deflection. Angles from stationary subjects progressed from 141 ± 9° to 120°. Peak normalized deflections, peak rates, and VCmax ranges were 0.075 – 0.171, 3.7 – 12.7 m/s, and 0.3 – 0.6 m/s with stationary airbag, respectively; ranges were 0.167 – 0.297, 7.4 – 18.3 m/s, and 0.7 – 3.0 m/s with airbag sled impact, respectively. Peak deflections were measured at angles between 99° – 135° and 98° – 125° for stationary and dynamic conditions, respectively. Because of deflection angle transience and localized injury response, both posterolateral and lateral injury metrics may be required for this boundary condition. Contrasted with flat rigid or anterolateral loading, biomechanical response to side airbag interaction may be augmented by peak normalized deflection or VCmax at 130°. PMID:21512911

Treadmill Training or Progressive Strength Training to Improve Walking in People with Multiple Sclerosis? A Randomized Parallel Group Trial.

PubMed

Braendvik, Siri Merete; Koret, Teija; Helbostad, Jorunn L; Lorås, Håvard; Bråthen, Geir; Hovdal, Harald Olav; Aamot, Inger Lise

2016-12-01

The most effective treatment approach to improve walking in people with multiple sclerosis (MS) is not known. The aim of this trial was to assess the efficacy of treadmill training and progressive strength training on walking in people with MS. A single blinded randomized parallel group trial was carried out. Eligible participants were adults with MS with Expanded Disability Status Scale score ≤6. A total of 29 participants were randomized and 28 received the allocated exercise intervention, treadmill (n = 13) or strength training (n = 15). Both groups exercised 30 minutes, three times a week for 8 weeks. Primary outcome was The Functional Ambulation Profile evaluated by the GAITRite walkway. Secondary outcomes were walking work economy and balance control during walking, measured by a small lightweight accelerometer connected to the lower back. Testing was performed at baseline and the subsequent week after completion of training. Two participants were lost to follow-up, and 11 (treadmill) and 15 (strength training) were left for analysis. The treadmill group increased their Functional Ambulation Profile score significantly compared with the strength training group (p = .037). A significant improvement in walking work economy (p = .024) and a reduction of root mean square of vertical acceleration (p = .047) also favoured the treadmill group. The results indicate that task-specific training by treadmill walking is a favourable approach compared with strength training to improve walking in persons with mild and moderate MS. Implications for Physiotherapy practice, this study adds knowledge for the decision of optimal treatment approaches in people with MS. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Graph Theory-Based Brain Connectivity for Automatic Classification of Multiple Sclerosis Clinical Courses.

PubMed

Kocevar, Gabriel; Stamile, Claudio; Hannoun, Salem; Cotton, François; Vukusic, Sandra; Durand-Dubief, Françoise; Sappey-Marinier, Dominique

2016-01-01

Purpose: In this work, we introduce a method to classify Multiple Sclerosis (MS) patients into four clinical profiles using structural connectivity information. For the first time, we try to solve this question in a fully automated way using a computer-based method. The main goal is to show how the combination of graph-derived metrics with machine learning techniques constitutes a powerful tool for a better characterization and classification of MS clinical profiles. Materials and Methods: Sixty-four MS patients [12 Clinical Isolated Syndrome (CIS), 24 Relapsing Remitting (RR), 24 Secondary Progressive (SP), and 17 Primary Progressive (PP)] along with 26 healthy controls (HC) underwent MR examination. T1 and diffusion tensor imaging (DTI) were used to obtain structural connectivity matrices for each subject. Global graph metrics, such as density and modularity, were estimated and compared between subjects' groups. These metrics were further used to classify patients using tuned Support Vector Machine (SVM) combined with Radial Basic Function (RBF) kernel. Results: When comparing MS patients to HC subjects, a greater assortativity, transitivity, and characteristic path length as well as a lower global efficiency were found. Using all graph metrics, the best F -Measures (91.8, 91.8, 75.6, and 70.6%) were obtained for binary (HC-CIS, CIS-RR, RR-PP) and multi-class (CIS-RR-SP) classification tasks, respectively. When using only one graph metric, the best F -Measures (83.6, 88.9, and 70.7%) were achieved for modularity with previous binary classification tasks. Conclusion: Based on a simple DTI acquisition associated with structural brain connectivity analysis, this automatic method allowed an accurate classification of different MS patients' clinical profiles.

Mass spectrometry of long-lived radionuclides

NASA Astrophysics Data System (ADS)

Becker, Johanna Sabine

2003-10-01

The capability of determining element concentrations at the trace and ultratrace level and isotope ratios is a main feature of inorganic mass spectrometry. The precise and accurate determination of isotope ratios of long-lived natural and artificial radionuclides is required, e.g. for their environmental monitoring and health control, for studying radionuclide migration, for age dating, for determining isotope ratios of radiogenic elements in the nuclear industry, for quality assurance and determination of the burn-up of fuel material in a nuclear power plant, for reprocessing plants, nuclear material accounting and radioactive waste control. Inorganic mass spectrometry, especially inductively coupled plasma mass spectrometry (ICP-MS) as the most important inorganic mass spectrometric technique today, possesses excellent sensitivity, precision and good accuracy for isotope ratio measurements and practically no restriction with respect to the ionization potential of the element investigated—therefore, thermal ionization mass spectrometry (TIMS), which has been used as the dominant analytical technique for precise isotope ratio measurements of long-lived radionuclides for many decades, is being replaced increasingly by ICP-MS. In the last few years instrumental progress in improving figures of merit for the determination of isotope ratio measurements of long-lived radionuclides in ICP-MS has been achieved by the application of a multiple ion collector device (MC-ICP-MS) and the introduction of the collision cell interface in order to dissociate disturbing argon-based molecular ions, to reduce the kinetic energy of ions and neutralize the disturbing noble gas ions (e.g. of 129Xe + for the determination of 129I). The review describes the state of the art and the progress of different inorganic mass spectrometric techniques such as ICP-MS, laser ablation ICP-MS vs. TIMS, glow discharge mass spectrometry, secondary ion mass spectrometry, resonance ionization mass spectrometry and accelerator mass spectrometry for the determination of long-lived radionuclides in quite different materials.

Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease.

PubMed

Yuan, Wei; Sanda, Miloslav; Wu, Jing; Koomen, John; Goldman, Radoslav

2015-02-26

Aberrant glycosylation of IgGs has been linked to human diseases, including liver disease. In this study, we have quantified plasma immunoglobulins in cirrhosis (CIR) and hepatocellular carcinoma (HCC) and employed a novel LC-MS-MRM assay to quantify glycoforms of IgG subclasses 1-4. Glycan oxonium ions and peptide-GlcNAc fragment ions were utilized to quantify the IgG glycoforms purified by affinity chromatography with normalization to the unique peptide for each IgG subclass. Our results indicate that HCC patients have increased circulating IgG1, IgG3, IgA1, and IgM compared to healthy controls; comparison of HCC and CIR patients shows that HCC patients have significantly higher concentration of IgG1 and IgM but lower concentration of IgG2. An increase in galactose-deficient core fucosylated glycoforms was consistently observed in CIR and HCC patients. The FA2G0 and FA2BG0 glycoforms increase approximately 2-fold in all IgG subclasses accompanied by a decrease in the FA2G2 glycoform. Fucosylation changes are less pronounced but we have detected increased degree of fucosylation in the IgG1 and IgG3 glycoforms. In conclusion, we have optimized a sensitive and selective LC-MS-MRM method for the quantification of immunoglobulin subclasses and their site specific glycoforms, demonstrating that both quantities and glycoforms of immunoglobulins change significantly in liver disease progression to HCC. We have demonstrated that both quantities and glycoforms of immunoglobulin subclasses change significantly in liver disease progression to HCC through quantitative study of immunoglobulin subclasses and their site specific glycoforms using a sensitive and selective LC-MS-MRM method. Redistribution of the glycoforms of specific immunoglobulin subclasses could have important implications for receptor mediated responses affecting the progression of liver disease. Copyright © 2015 Elsevier B.V. All rights reserved.

New horizons for multiple sclerosis therapeutics: milestones in the development of ocrelizumab.

PubMed

Frau, Jessica; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Cocco, Eleonora

2018-01-01

Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system, and both T and B cells are involved in its pathogenesis. The vast majority of disease-modifying drugs used for MS act on the inflammatory component of the disease and are approved for use in relapsing-remitting (RR) patients. Ocrelizumab (OCR) is the only MS drug that has been approved by the US Food and Drug Administration (FDA) not only for patients with RRMS but also for patients with primary progressive (PP) MS. OCR is a humanized anti-CD20 monoclonal antibody that can deplete the targeted B cells through antibody-dependent cellular cytotoxicity. Treatment involves administration by intravenous infusion every 6 months. OCR can cause long-lasting B-cell depletion and change the pool of reconstituted B cells. Phase III clinical trials have confirmed the results of previous Phase II studies. In particular, OPERA I and II trials, which were performed in patients with RRMS, showed a reduction in the annualized relapse rate, the risk of disability progression, and the number of new/enlarging T2 lesions and enhancing lesions measured using brain magnetic resonance. The ORATORIO trial, performed in PP subjects, showed that OCR can reduce disability progression, improve performance on the timed 25-foot walk, and decrease the total volume of T2 lesions and the mean number of new or enlarging T2 lesions. The most frequent adverse events were the infusion-related reactions and infections. Infections were mostly nasopharyngitis, as well as upper respiratory and urinary tract infections. OCR gives no indication for severe or opportunistic infections. There is not a clear increased risk of malignancies. Nevertheless, it could not be excluded. Real-life registries will provide more information about the long-term safety, the risk of exposure during pregnancy, and the risk of rare adverse events. In this review, we analyze the evidence regarding the efficacy and the safety of OCR.

Sativex® effects on promoter methylation and on CNR1/CNR2 expression in peripheral blood mononuclear cells of progressive multiple sclerosis patients.

PubMed

Santoro, Massimo; Mirabella, Massimiliano; De Fino, Chiara; Bianco, Assunta; Lucchini, Matteo; Losavio, Francesco; Sabino, Andrea; Nociti, Viviana

2017-08-15

Multiple sclerosis (MS) is a chronic demyelinating central nervous system (CNS) disease that involve oligodendrocyte loss and failure to remyelinate damaged brain areas causing a progressive neurological disability. Studies in MS mouse model suggest that cannabinoids ameliorate symptoms as spasticity, tremor and pain reducing inflammation via cannabinoid-mediated system. The aim of our study is to investigate the changes in cannabinoid type 1 (CNR1) and 2 (CNR2) receptors mRNA expression levels and promoter methylation in peripheral blood mononuclear cells (PBMCs) of MS secondary progressive (MSS-SP) patients treated with Sativex®. Our cohort included MSS-SP patients, that at the time of Sativex® treatment, are treated (n=7), not treated (n=11) or that had terminated interferon-β-1b (IFN-β-1b) therapy (n=12). By Methylation Sensitive High Resolution Melting (MS-HRM), we characterized the methylation profile of CNR1 and CNR2 promoter region, while the relative mRNA transcript levels of these two genes were evaluated in the same samples by Quantitative Real-Time PCR (qRT-PCR) analysis. We did not find different pattern of cytosine-phosphate-guanine (CpG) methylation in the CNR1/CNR2 promoter region of all MSS-SP patients treated with Sativex®. In addition, CNR1 and CNR2 expression did not significantly differ in MSS-SP patients not treated with IFN-β-1b vs. them that have suspended, while in MSS-SP patients treated with IFN-β-1b during Sativex® therapy we found a specific decrease of the CNR2 expression levels. These results suggest that the different expression of cannabinoid receptors by Sativex® treatment in leukocytes might be regulated through a molecular mechanism that involve interferon modulation. Copyright © 2017 Elsevier B.V. All rights reserved.

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

PubMed

Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

2015-04-29

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

MRI in the assessment and monitoring of multiple sclerosis: an update on best practice

PubMed Central

Kaunzner, Ulrike W.; Gauthier, Susan A.

2017-01-01

Magnetic resonance imaging (MRI) has developed into the most important tool for the diagnosis and monitoring of multiple sclerosis (MS). Its high sensitivity for the evaluation of inflammatory and neurodegenerative processes in the brain and spinal cord has made it the most commonly used technique for the evaluation of patients with MS. Moreover, MRI has become a powerful tool for treatment monitoring, safety assessment as well as for the prognostication of disease progression. Clinically, the use of MRI has increased in the past couple decades as a result of improved technology and increased availability that now extends well beyond academic centers. Consequently, there are numerous studies supporting the role of MRI in the management of patients with MS. The aim of this review is to summarize the latest insights into the utility of MRI in MS. PMID:28607577

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, Erin Shammel; Burnum-Johnson, Kristin E.; Jacobs, Jon M.

Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is an imperative goal for the field of medicine. While mass spectrometry (MS)-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry (IMS) separations [1, 2] with liquid chromatography (LC) andmore » MS to dramatically increase measurement sensitivity and throughput, further enabling future MS-based clinical applications. An initial application of the LC-IMS-MS platform for the analysis of blood serum samples from stratified post-liver transplant patients with recurrent fibrosis progression illustrates its potential utility for disease characterization and use in personalized medicine [3, 4].« less

NASA Multidisciplinary Design and Analysis Fellowship Program

NASA Technical Reports Server (NTRS)

1995-01-01

This report is a Year 1 interim report of the progress on the NASA multidisciplinary Design and Analysis Fellowship Program covering the period, January 1, 1995 through September 30, 1995. It summarizes progress in establishing the MDA Fellowship Program at Georgia Tech during the initial year. Progress in the advertisement of the program, recruiting results for the 1995-96 academic year, placement of the Fellows in industry during Summer 1995, program development at the M.S. and Ph.D. levels, and collaboration and dissemination of results are summarized in this report. Further details of the first year's progress will be included in the report from the Year 1 Workshop to be held at NASA Langley on December 7-8, 1995.

Detection of Changes in the Medicago sativa Retinoblastoma-Related Protein (MsRBR1) Phosphorylation During Cell Cycle Progression in Synchronized Cell Suspension Culture.

PubMed

Ayaydin, Ferhan; Kotogány, Edit; Ábrahám, Edit; Horváth, Gábor V

2017-01-01

Deepening our knowledge on the regulation of the plant cell division cycle depends on techniques that allow for the enrichment of cell populations in defined cell cycle phases. Synchronization of cell division can be achieved using different plant tissues; however, well-established cell suspension cultures provide large amount of biological sample for further analyses. Here, we describe the methodology of the establishment, propagation, and analysis of a Medicago sativa suspension culture that can be used for efficient synchronization of the cell division. A novel 5-ethynyl-2'-deoxyuridine (EdU)-based method is used for the estimation of cell fraction that enters DNA synthesis phase of the cell cycle and we also demonstrate the changes in the phosphorylation level of Medicago sativa retinoblastoma-related protein (MsRBR1) during cell cycle progression.

Spinal cord lesions of progressive multifocal leukoencephalopathy in an acquired immunodeficiency syndrome patient.

PubMed

Bernal-Cano, F; Joseph, J T; Koralnik, I J

2007-10-01

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. This disease is caused by a reactivation of the polyomavirus JC (JCV). Clinical presentation can be variable from patient to patient as lesions can occur anywhere in the CNS white matter; however, they appear to spare the optic nerves and the spinal cord. The authors present a case of PML in the setting of acquired immunodeficiency syndrome (AIDS) who developed PML lesions in the spinal cord, discovered during the postmortem examination. This finding is significant because PML has recently been diagnosed in patients with multiple sclerosis (MS) treated with the novel immunomodulatory medication natalizumab. Indeed, spinal cord lesions are frequent in MS. Therefore clinicians should be aware that in addition to the brain, PML may also affect the spinal cord white matter.

Efficacy of Fish Oil on Serum of TNFα, IL-1β, and IL-6 Oxidative Stress Markers in Multiple Sclerosis Treated with Interferon Beta-1b

PubMed Central

Ramirez-Ramirez, V.; Macias-Islas, M. A.; Ortiz, G. G.; Pacheco-Moises, F.; Torres-Sanchez, E. D.; Sorto-Gomez, T. E.; Cruz-Ramos, J. A.; Orozco-Aviña, G.; Celis de la Rosa, A. J.

2013-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system. Oxidative stress is also thought to promote tissue damage in multiple sclerosis. Current research findings suggest that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapenta-enoic acid (EPA) and docosahexaenoic acid (DHA) contained in fish oil may have anti-inflammatory, antioxidant, and neuroprotective effects. The aim of the present work was to evaluate the efficacy of fish oil supplementation on serum proinflammatory cytokine levels, oxidative stress markers, and disease progression in MS. 50 patients with relapsing-remitting MS were enrolled. The experimental group received orally 4 g/day of fish oil for 12 months. The primary outcome was serum TNFα levels; secondary outcomes were IL-1β 1b, IL-6, nitric oxide catabolites, lipoperoxides, progression on the expanded disability status scale (EDSS), and annualized relapses rate (ARR). Fish oil treatment decreased the serum levels of TNFα, IL-1β, IL-6, and nitric oxide metabolites compared with placebo group (P ≤ 0.001). There was no significant difference in serum lipoperoxide levels during the study. No differences in EDSS and ARR were found. Conclusion. Fish oil supplementation is highly effective in reducing the levels of cytokines and nitric oxide catabolites in patients with relapsing-remitting MS. PMID:23861993

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

PubMed

Hagemeier, Jesper; Ramanathan, Murali; Schweser, Ferdinand; Dwyer, Michael G; Lin, Fuchun; Bergsland, Niels; Weinstock-Guttman, Bianca; Zivadinov, Robert

2018-01-01

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE : rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

Do Cartilage Repair Procedures Prevent Degenerative Meniscus Changes? Longitudinal T1ρ and Morphological Evaluation at 3.0T

PubMed Central

Jungmann, Pia M.; Li, Xiaojuan; Nardo, Lorenzo; Subburaj, Karupppasamy; Lin, Wilson; Ma, C. Benjamin; Majumdar, Sharmila; Link, Thomas M.

2014-01-01

Background Cartilage repair (CR) procedures are widely accepted for treatment of isolated cartilage defects at the knee joint. However, it is not well known whether these procedures prevent degenerative joint disease. Hypothesis/Purpose CR procedures prevent accelerated qualitative and quantitative progression of meniscus degeneration in individuals with focal cartilage defects. Study Design Cohort Study; Level of evidence 2b Methods A total of 94 subjects were studied. CR procedures were performed on 34 patients (n=16 osteochondral transplantation, n=18 microfracture); 34 controls were matched. An additional 13 patients received CR and anterior cruciate ligament (ACL) reconstruction (CR&ACL) and 13 patients received only ACL reconstruction. 3.0T MRI with T1ρ mapping and sagittal fat-saturated intermediate-weighted fast spin echo (FSE) sequences was performed to analyze menisci quantitatively and qualitatively (Whole-Organ Magnetic Resonance Imaging Score, WORMS). CR and CR&ACL patients were examined 4 months (n=34; n=13), 1 (n=21; n=8) and 2 (n=9; n=5) years post CR. Control subjects were scanned at baseline and after 1 and 2 years, ACL patients after 1 and 2 years. Results At baseline, global meniscus T1ρ values were higher in individuals with CR (14.2±0.6ms; P=0.004) and in individuals with CR&ACL (17.1±0.9ms; P<0.001) when compared to controls (12.8±0.6ms). After two years, there was a statistical difference between T1ρ at the overlying meniscus above cartilage defects (16.4±1.0ms) and T1ρ of the subgroup of control knees without cartilage defects (12.1±0.8ms; P<0.001) and a statistical trend to the CR group (13.3±1.0 ms; P=0.088). At baseline, 35% of subjects with CR showed morphological meniscus tears at the overlying meniscus; 10% of CR subjects showed an increase of WORMS meniscus score within the first year, none progressed in the second year. Control subjects with (without) cartilage defects showed meniscus tears in 30% (5%) at baseline; 38% (19%) increased within the first, and 15% (10%) within the second year. Conclusions This study identified more severe meniscus degeneration after CR surgery compared to controls. However, progression of T1ρ values was not observed from 1 to 2 years after surgery. These results suggest, that CR may prevent degenerative meniscus changes. PMID:23104606

Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space.

PubMed

Howell, Owain W; Schulz-Trieglaff, Elena Katharina; Carassiti, Daniele; Gentleman, Steven M; Nicholas, Richard; Roncaroli, Federico; Reynolds, Richard

2015-10-01

Multiple sclerosis (MS) is a progressive inflammatory neurological disease affecting myelin, neurons and glia. Demyelination and neurodegeneration of cortical grey matter contribute to a more severe disease, and inflammation of the forebrain meninges associates with pathology of the underlying neocortical grey matter, particularly in deep sulci. We assessed the extent of meningeal inflammation of the cerebellum, another structure with a deeply folded anatomy, to better understand the association between subarachnoid inflammation and grey matter pathology in progressive MS. We examined demyelinating and neuronal pathology in the context of meningeal inflammation in cerebellar tissue blocks from a cohort of 27 progressive MS cases previously characterized on the basis of the absence/presence of lymphoid-like aggregates in the forebrain meninges, in comparison with 11 non-neurological controls. Demyelination and meningeal inflammation of the cerebellum was greatest in those cases previously characterized as harbouring lymphoid-like structures in the forebrain regions. Meningeal inflammation was mild to moderate in cerebellar tissue blocks, and no lymphoid-like structures were seen. Quantification of meningeal macrophages, CD4+, CD8+ T lymphocytes, B cells and plasma cells revealed that the density of meningeal macrophages associated with microglial activation in the grey matter, and the extent of grey matter demyelination correlated with the density of macrophages and plasma cells in the overlying meninges, and activated microglia of the parenchyma. These data suggest that chronic inflammation is widespread throughout the subarachnoid space and contributes to a more severe subpial demyelinating pathology in the cerebellum. © 2014 British Neuropathological Society.

Persistent activation of microglia and NADPH drive hippocampal dysfunction in experimental multiple sclerosis

PubMed Central

Di Filippo, Massimiliano; de Iure, Antonio; Giampà, Carmela; Chiasserini, Davide; Tozzi, Alessandro; Orvietani, Pier Luigi; Ghiglieri, Veronica; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Mancini, Andrea; Costa, Cinzia; Sarchielli, Paola; Fusco, Francesca Romana; Calabresi, Paolo

2016-01-01

Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression. PMID:26887636

Role of vitamin D in regulating the neural stem cells of mouse model with multiple sclerosis.

PubMed

Gu, S-G; Wang, C-J; Zhao, G; Li, G-Y

2015-11-01

Multiple sclerosis (MS) is an autoimmune disease that results with a damaged myelin sheath as a result, there is an impairment of nerve impulse conduction. The medication for MS is able to delay its progression, but complete recovery is impossible. Recent studies with neural stem cells have promising results in treating as well as to recover the damaged nerves, but research on in vivo model system is limited in this aspect. Here we are able to successfully establish an MS mice model by injecting with myelin basic protein and we studied the neural stem cell response in supplement with vitamin D. Through histology we provide strong evidence that the MS pathogenesis is reverted on response to vitamin D. We also identified through immunohistochemistry and western blotting that the vitamin D has the ability to trigger neural stem cells, and thereby it assist in recovery from MS. Further, their roles in preventing as well as delaying the MS development are also proven. The role of vitamin D has also cross checked with the help of tunnel assay. Overall, our results conclude that the lesion associated apoptotic signals are reduced on administrated with vitamin D. The present data help to design a new therapeutic intervention to cure MS.

Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

PubMed Central

Damal, Kavitha; Stoker, Emily; Foley, John F

2013-01-01

Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics. PMID:24324326

Advanced Mass Spectrometric Methods for the Rapid and Quantitative Characterization of Proteomes

DOE PAGES

Smith, Richard D.

2002-01-01

Progress is reviewedmore » towards the development of a global strategy that aims to extend the sensitivity, dynamic range, comprehensiveness and throughput of proteomic measurements based upon the use of high performance separations and mass spectrometry. The approach uses high accuracy mass measurements from Fourier transform ion cyclotron resonance mass spectrometry (FTICR) to validate peptide ‘accurate mass tags’ (AMTs) produced by global protein enzymatic digestions for a specific organism, tissue or cell type from ‘potential mass tags’ tentatively identified using conventional tandem mass spectrometry (MS/MS). This provides the basis for subsequent measurements without the need for MS/ MS. High resolution capillary liquid chromatography separations combined with high sensitivity, and high resolution accurate FTICR measurements are shown to be capable of characterizing peptide mixtures of more than 10 5 components. The strategy has been initially demonstrated using the microorganisms Saccharomyces cerevisiae and Deinococcus radiodurans. Advantages of the approach include the high confidence of protein identification, its broad proteome coverage, high sensitivity, and the capability for stableisotope labeling methods for precise relative protein abundance measurements. Abbreviations : LC, liquid chromatography; FTICR, Fourier transform ion cyclotron resonance; AMT, accurate mass tag; PMT, potential mass tag; MMA, mass measurement accuracy; MS, mass spectrometry; MS/MS, tandem mass spectrometry; ppm, parts per million.« less

Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action.

PubMed

Damal, Kavitha; Stoker, Emily; Foley, John F

2013-01-01

Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics.

Mechanosensitive channels are activated by stress in the actin stress fibres, and could be involved in gravity sensing in plants.

PubMed

Tatsumi, H; Furuichi, T; Nakano, M; Toyota, M; Hayakawa, K; Sokabe, M; Iida, H

2014-01-01

Mechanosensitive (MS) channels are expressed in a variety of cells. The molecular and biophysical mechanism involved in the regulation of MS channel activities is a central interest in basic biology. MS channels are thought to play crucial roles in gravity sensing in plant cells. To date, two mechanisms have been proposed for MS channel activation. One is that tension development in the lipid bilayer directly activates MS channels. The second mechanism proposes that the cytoskeleton is involved in the channel activation, because MS channel activities are modulated by pharmacological treatments that affect the cytoskeleton. We tested whether tension in the cytoskeleton activates MS channels. Mammalian endothelial cells were microinjected with phalloidin-conjugated beads, which bound to stress fibres, and a traction force to the actin cytoskeleton was applied by dragging the beads with optical tweezers. MS channels were activated when the force was applied, demonstrating that a sub-pN force to the actin filaments activates a single MS channel. Plants may use a similar molecular mechanism in gravity sensing, since the cytoplasmic Ca(2+) concentration increase induced by changes in the gravity vector was attenuated by potential MS channel inhibitors, and by actin-disrupting drugs. These results support the idea that the tension increase in actin filaments by gravity-dependent sedimentation of amyloplasts activates MS Ca(2+) -permeable channels, which can be the molecular mechanism of a Ca(2+) concentration increase through gravistimulation. We review recent progress in the study of tension sensing by actin filaments and MS channels using advanced biophysical methods, and discuss their possible roles in gravisensing. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

Epidemiological and clinical characteristics of multiple sclerosis in paediatric population in Slovenia: A descriptive nation-wide study.

PubMed

Bizjak, Neli; Osredkar, Damjan; Perković Benedik, Mirjana; Šega Jazbec, Saša

2017-11-01

Although multiple sclerosis usually affects young adults, paediatric-onset multiple sclerosis (pMS) is increasingly recognized in the past ten years. The aim of the present study was to evaluate the incidence of pMS in Slovenia and to characterize the clinical, laboratory and neuroradiological characteristics of pMS at the disease onset. We performed a national retrospective descriptive study including all patients diagnosed with pMS between January 1992 and June 2017. We reviewed data of all patients younger than 18 years at the first demyelinating event. The estimated incidence of pMS was 0.66/100,000 children per year. We included 61 patients (77% were female) with a median age at diagnosis of 16.3 years. In 4 patients, onset of pMS was before the age of 12 years old (childhood-onset pMS). Relapsing-remitting multiple sclerosis was most prevalent, with only 2 patients presenting a primary progressive pMS. Polysymptomatic pMS was found at onset in 59% of patients and monosymptomatic in 41%. In the cerebrospinal fluid study, 88% of patients had positive oligoclonal bands. Brain magnetic resonance imaging studies showed a predominant supratentorial involvement (100% of patients). The clinical pattern of pMS in our cohort of patients was characterized by polysymptomatic presentation and predominantly sensory symptoms at onset, developing a relapsing-remitting pMS pattern. It is important to gather more information about the incidence of pMS and its initial presentation and clinical course to improve early recognition and appropriate initiation of immunomodulatory treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic Variation near IRF8 is Associated with Serologic and Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis

PubMed Central

Chrabot, Beverly S.; Kariuki, Silvia N.; Zervou, Maria I.; Feng, Xuan; Arrington, Jasmine; Jolly, Meenakshi; Boumpas, Dimitrios T.; Reder, Anthony T.; Goulielmos, George N.; Niewold, Timothy B.

2013-01-01

Alleles of IRF8 are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While high type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles which have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-dsDNA autoantibodies in SLE patients (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in PBMC from anti-dsDNA negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance. PMID:23965942

Difference gel electrophoresis (DiGE) identifies differentially expressed proteins in endoscopically-collected pancreatic fluid

PubMed Central

Paulo, Joao A.; Lee, Linda S.; Banks, Peter A.; Steen, Hanno; Conwell, Darwin L.

2012-01-01

Alterations in the pancreatic fluid proteome of individuals with chronic pancreatitis may offer insights into the development and progression of the disease. The endoscopic pancreas function test (ePFT) can safely collect large volumes of pancreatic fluid that are potentially amenable to proteomic analyses using difference gel electrophoresis (DiGE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pancreatic fluid was collected endoscopically using the ePFT method following secretin stimulation from three individuals with severe chronic pancreatitis and three chronic abdominal pain controls. The fluid was processed to minimize protein degradation and the protein profiles of each cohort, as determined by DiGE and LC-MS/MS, were compared. This DiGE-LC-MS/MS analysis reveals proteins that are differentially expressed in chronic pancreatitis compared to chronic abdominal pain controls. Proteins with higher abundance in pancreatic fluid from chronic pancreatitis individuals include: actin, desmoplankin, alpha-1-antitrypsin, SNC73, and serotransferrin. Those of relatively lower abundance include carboxypeptidase B, lipase, alpha-1-antichymotrypsin, alpha-2-macroglobulin, Arp2/3 subunit 4, glyceraldehyde-3-phosphate dehydrogenase, and protein disulfide isomerase. Endoscopic collection (ePFT) in tandem with DiGE-LC-MS/MS is a suitable approach for pancreatic fluid proteome analysis, however, further optimization of our protocol, as outlined herein, may improve proteome coverage in future analyses. PMID:21792986

Peptidomics: the integrated approach of MS, hyphenated techniques and bioinformatics for neuropeptide analysis.

PubMed

Boonen, Kurt; Landuyt, Bart; Baggerman, Geert; Husson, Steven J; Huybrechts, Jurgen; Schoofs, Liliane

2008-02-01

MS is currently one of the most important analytical techniques in biological and medical research. ESI and MALDI launched the field of MS into biology. The performance of mass spectrometers increased tremendously over the past decades. Other technological advances increased the analytical power of biological MS even more. First, the advent of the genome projects allowed an automated analysis of mass spectrometric data. Second, improved separation techniques, like nanoscale HPLC, are essential for MS analysis of biomolecules. The recent progress in bioinformatics is the third factor that accelerated the biochemical analysis of macromolecules. The first part of this review will introduce the basics of these techniques. The field that integrates all these techniques to identify endogenous peptides is called peptidomics and will be discussed in the last section. This integrated approach aims at identifying all the present peptides in a cell, organ or organism (the peptidome). Today, peptidomics is used by several fields of research. Special emphasis will be given to the identification of neuropeptides, a class of short proteins that fulfil several important intercellular signalling functions in every animal. MS imaging techniques and biomarker discovery will also be discussed briefly.