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(+).

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.

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

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.

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.

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

Phonological fluency strategy of switching differentiates relapsing-remitting and secondary progressive multiple sclerosis patients.

PubMed

Messinis, L; Kosmidis, M H; Vlahou, C; Malegiannaki, A C; Gatzounis, G; Dimisianos, N; Karra, A; Kiosseoglou, G; Gourzis, P; Papathanasopoulos, P

2013-01-01

The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls.

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with Trichuris suis ova therapy.

PubMed

Rosche, Berit; Werner, Jonas; Benzel, Friderike Joëlle; Harms, Lutz; Danker-Hopfe, Heidi; Hellweg, Rainer

2013-01-01

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05). © B. Rosche et al., published by EDP Sciences, 2013.

Secondary conditions among males with Duchenne or Becker muscular dystrophy

PubMed Central

Latimer, Rebecca; Street, Natalie; Conway, Kristin Caspers; James, Kathy; Cunniff, Christopher; Oleszek, Joyce; Fox, Deborah; Ciafaloni, Emma; Westfield, Christina; Paramsothy, Pangaja

2017-01-01

Duchenne and Becker muscular dystrophy are X-linked neuromuscular disorders characterized by progressive muscle degeneration. Despite the involvement of multiple systems, secondary conditions among affected males have not been comprehensively described. Two hundred and nine caregivers of affected males (aged 3–31 years) identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network completed a mailed survey that included questions about secondary conditions impacting multiple body functions. The five most commonly reported conditions in males with Duchenne were cognitive deficits (38.4%), constipation (31.7%), anxiety (29.3%), depression (27.4%), and obesity (19.5%). Higher frequencies of anxiety, depression, and kidney stones, were found among non-ambulatory males compared to ambulatory males. Attention deficit hyperactivity disorder was more common in ambulatory than non-ambulatory males. These data support clinical care recommendations for monitoring of patients with Duchenne or Becker muscular dystrophy by a multidisciplinary team to prevent and treat conditions that may be secondary to the diagnosis. PMID:28393671

Current concepts on burn wound conversion – a review of recent advances in understanding the secondary progressions of burns

PubMed Central

Salibian, Ara A.; Del Rosario, Angelica Tan; De Almeida Moura Severo, Lucio; Nguyen, Long; Banyard, Derek A.; Toranto, Jason D.; Evans, Gregory R.D.; Widgerow, Alan D.

2016-01-01

Burn wound conversion describes the process by which superficial partial thickness burns convert into deeper burns necessitating surgical intervention. Fully understanding and thus controlling this phenomenon continues to defy burn surgeons. However, potentially guiding burn wound progression so as to obviate the need for surgery while still bringing about healing with limited scarring is the major unmet challenge. Comprehending the pathophysiologic background contributing to deeper progression of these burns is an essential prerequisite to planning any intervention. In this study, a review of articles examining burn wound progression over the last five years was conducted to analyze trends in recent burn progression research, determine changes in understanding of the pathogenesis of burn conversion, and subsequently examine the direction for future research in developing therapies. The majority of recent research focuses on applying therapies from other disease processes to common underlying pathogenic mechanisms in burn conversion. While ischemia, inflammation, and free oxygen radicals continue to demonstrate a critical role in secondary necrosis, novel mechanisms such as autophagy have also been shown to contribute affect significantly burn progression significantly. Further research will have to determine whether multiple mechanisms should be targeted when developing clinical therapies. PMID:26787127

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.

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

PubMed

Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-Scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-Guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; McCombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-Tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Luis Sanchez-Menoyo, Jose; Laura Saladino, Maria; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

2017-09-01

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

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.

Understanding the impact of relapses in the overall course of MS; refinement of the 2 stage natural history model.

PubMed

Scott, Thomas F

2017-04-15

Recent studies suggest a need for refinement of the traditional two phase model of relapse onset multiple sclerosis (RMS) to include dynamically changing subgroups within the broad category of secondary progressive MS (SPMS). These studies challenge the traditional notion that relapses play a minor role in comparison to a secondary progressive (perhaps degenerative) process. Patients fulfilling the broad definition for SPMS may take several courses, including variable rates and patterns of overall worsening. New paradigms or models for mapping the trajectory of disability in RMS and SPMS (clinical phenotyping), including periods of remission, may impact our understanding of the underlying pathology, and will be important in assessing treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

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

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

'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.

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.

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.

[The application of high-frequency and iTBS transcranial magnetic stimulation for the treatment of spasticity in the patients presenting with secondary progressive multiple sclerosis].

PubMed

Korzhova, J E; Chervyakov, A V; Poydasheva, A G; Kochergin, I A; Peresedova, A V; Zakharova, M N; Suponeva, N A; Chernikova, L A; Piradov, M A

Spasticity is considered to be a common manifestation of multiple sclerosis. Muscle relaxants are not sufficiently effective; more than that, some of them often cause a variety of adverse reactions. Transcranial magnetic stimulation (TMS) can be a promising new tool for the treatment of spasticity. The objective of the present study was to compare the effectiveness of the two TMS protocols: rhythmic (high-frequency) TMS (rTMS) and stimulation with the theta bursts (iTBS) in terms of their ability to reduce spasticity in the patients presenting with multiple sclerosis. Twenty two patients with secondary-progressive multiple sclerosis were pseudo-randomized into two groups: those in the first (high-frequency) group received the treatment with the use of rTMS therapy at a frequency of 10 Hz; the patients of the second group, underwent stimulation with the theta bursts (iTBS). All the patients received 10 sessions of either stimulation applied to the primary motor area (M1) of both legs. The effectiveness of TMS protocols was evaluated before therapy and after 10 sessions of stimulation based on the Modified Ashworth scale (MAS), the expanded disability status scale (EDSS), and the Kurtzke functional scale (Kfs). In addition, the patients were interviewed before treatment, after 10 rTMS sessions, immediately after and within 2 and 12 weeks after the completion of the treatment using questionnaires for the evaluation of spasticity (SESS) , fatigue, and dysfunction of the pelvic organs (severity of defecation and urination disorders), fatigue. The study has demonstrated a significant reduction in spasticity in the patients of both groups at the end of the TMS protocol based on the MAS scale. There was no significant difference between the outcomes of the two protocols. Both had positive effect on the concomitant «non-motor» symptoms (fatigue, dysfunction of the pelvic organs). High-frequency transcranial magnetic stimulation (10 sessions of rTMS therapy at a frequency of 10 Hz) and stimulation with the theta-bursts applied to the M1 area in both legs can be an effective alternative treatment of spasticity in the patients with secondary-progressive multiple sclerosis. Further research is needed to detect more accurately the differences between the outcomes of the two stimulation protocols and the development of indications for their application on an individual basis.

Current concepts on burn wound conversion-A review of recent advances in understanding the secondary progressions of burns.

PubMed

Salibian, Ara A; Rosario, Angelica Tan Del; Severo, Lucio De Almeida Moura; Nguyen, Long; Banyard, Derek A; Toranto, Jason D; Evans, Gregory R D; Widgerow, Alan D

2016-08-01

Burn wound conversion describes the process by which superficial partial thickness burns convert into deeper burns necessitating surgical intervention. Fully understanding and thus controlling this phenomenon continues to defy burn surgeons. However, potentially guiding burn wound progression so as to obviate the need for surgery while still bringing about healing with limited scarring is the major unmet challenge. Comprehending the pathophysiologic background contributing to deeper progression of these burns is an essential prerequisite to planning any intervention. In this study, a review of articles examining burn wound progression over the last five years was conducted to analyze trends in recent burn progression research, determine changes in understanding of the pathogenesis of burn conversion, and subsequently examine the direction for future research in developing therapies. The majority of recent research focuses on applying therapies from other disease processes to common underlying pathogenic mechanisms in burn conversion. While ischemia, inflammation, and free oxygen radicals continue to demonstrate a critical role in secondary necrosis, novel mechanisms such as autophagy have also been shown to contribute affect significantly burn progression significantly. Further research will have to determine whether multiple mechanisms should be targeted when developing clinical therapies. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Cognitive and Language Deficits in Multiple Sclerosis: Comparison of Relapsing Remitting and Secondary Progressive Subtypes

PubMed Central

Ntoskou, Katerina; Messinis, Lambros; Nasios, Grigorios; Martzoukou, Maria; Makris, Giorgos; Panagiotopoulos, Elias; Papathanasopoulos, Panagiotis

2018-01-01

Objective: The objective of this study was to investigate the pattern and severity of cognitive and language impairment in Greek patients with Relapsing-remitting (RRMS) and Secondary Progressive Multiple Sclerosis (SPMS), relative to control participants. Method: A prospective study was conducted in 27 patients with multiple sclerosis (PwMS), (N= 15) with RRMS, (N= 12) with SPMS, and (N= 12) healthy controls. All participants were assessed with a flexible comprehensive neuropsychological – language battery of tests that have been standardized in Greece and validated in Greek MS patients. They were also assessed on measures of disability (Expanded Disability Status Scale; EDSS), fatigue (Fatigue Severity Scale; FSS) and depression (Beck Depression Inventory - fast screen; BDI-FS). Results: Our results revealed that groups were well matched on baseline demographic and clinical characteristics. The two clinical groups (RRMS; SPMS) did not differ on overall global cognitive impairment but differed in the initial encoding of verbal material, mental processing speed, response inhibition and set-shifting. RRMS patients differed from controls in the initial encoding of verbal material, learning curve, delayed recall of verbal information, processing speed, and response inhibition. SPMS patients differed in all utilized measures compared to controls. Moreover, we noted increased impairment frequency on individualized measures in the progressive SPMS group. Conclusion: We conclude that MS patients, irrespective of clinical subtype, have cognitive deficits compared to healthy participants, which become increasingly worse when they convert from RRMS to SPMS.On the contrary,the pattern of impairment remains relatively stable. PMID:29576812

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.

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis.

PubMed

Romme Christensen, Jeppe; Börnsen, Lars; Khademi, Mohsen; Olsson, Tomas; Jensen, Poul Erik; Sørensen, Per Soelberg; Sellebjerg, Finn

2013-06-01

The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

Ensemble-based prediction of RNA secondary structures.

PubMed

Aghaeepour, Nima; Hoos, Holger H

2013-04-24

Accurate structure prediction methods play an important role for the understanding of RNA function. Energy-based, pseudoknot-free secondary structure prediction is one of the most widely used and versatile approaches, and improved methods for this task have received much attention over the past five years. Despite the impressive progress that as been achieved in this area, existing evaluations of the prediction accuracy achieved by various algorithms do not provide a comprehensive, statistically sound assessment. Furthermore, while there is increasing evidence that no prediction algorithm consistently outperforms all others, no work has been done to exploit the complementary strengths of multiple approaches. In this work, we present two contributions to the area of RNA secondary structure prediction. Firstly, we use state-of-the-art, resampling-based statistical methods together with a previously published and increasingly widely used dataset of high-quality RNA structures to conduct a comprehensive evaluation of existing RNA secondary structure prediction procedures. The results from this evaluation clarify the performance relationship between ten well-known existing energy-based pseudoknot-free RNA secondary structure prediction methods and clearly demonstrate the progress that has been achieved in recent years. Secondly, we introduce AveRNA, a generic and powerful method for combining a set of existing secondary structure prediction procedures into an ensemble-based method that achieves significantly higher prediction accuracies than obtained from any of its component procedures. Our new, ensemble-based method, AveRNA, improves the state of the art for energy-based, pseudoknot-free RNA secondary structure prediction by exploiting the complementary strengths of multiple existing prediction procedures, as demonstrated using a state-of-the-art statistical resampling approach. In addition, AveRNA allows an intuitive and effective control of the trade-off between false negative and false positive base pair predictions. Finally, AveRNA can make use of arbitrary sets of secondary structure prediction procedures and can therefore be used to leverage improvements in prediction accuracy offered by algorithms and energy models developed in the future. Our data, MATLAB software and a web-based version of AveRNA are publicly available at http://www.cs.ubc.ca/labs/beta/Software/AveRNA.

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.

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

PubMed Central

Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

2016-01-01

Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

Syphilis: an unusual manifestation?

PubMed Central

Bezalely, Shai; Jacob, Giris; Flusser, Gideon; Ablin, Jacob

2014-01-01

Syphilis is a widely investigated infectious venereal disease with varied presentations frequently mimicking other diseases. It progresses in distinct, well-characterised stages: early (primary and secondary), latent, and late (tertiary), each stage having its own unique presentations. However, there has been increasing evidence of atypical presentations. We describe one such presentation of early syphilis in its secondary stage. A man in his late 20s presented with a rash (which is typical of the secondary stage) and with bone pain with multiple lytic lesions (which is rare in the secondary stage but more typical of the tertiary stage). The patient was successfully treated for secondary syphilis. On the basis of our case, and on analysis of other case reports and research of early-stage syphilitic bone involvement, we conclude that the true incidence of bone involvement in early-stage syphilis may be higher than has been previously appreciated, and thus may be under-recognised and underdiagnosed. PMID:25239989

The Longer They Stay the Less Talented They Perceive They Are: Females' Talent Based on Approaches to Learning

ERIC Educational Resources Information Center

Bowles, Terry

2012-01-01

A cohort of female adolescents from 11 to 18 Years of age (n = 325) completed a questionnaire based on Gardner's theory of multiple intelligences (Gardner, 1999) to examine their perception of their talents as they progressed through secondary school. Results showed that the highest ranking talents were Physical and Sport Activity, and Language…

Delayed Development of Multiple Pancreaticoduodenal Arcade Pseudoaneurysms after Abdominal Trauma.

PubMed

Prosper, Ashley; Saremi, Farhood

2016-10-01

This case report demonstrates development and progressive enlargement of multiple pancreaticoduodenal arcade pseudoaneurysms using computed tomography angiographies over a period of 5 weeks after abdominal trauma. The mechanism of pseudoaneurysm formation, as shown by serial imaging, attributed to preexisting celiac axis stenosis by the median arcuate ligament, posttraumatic celiac artery dissection, and secondary occlusion of proper hepatic artery resulting in elevation of pressure and flow in the pancreaticoduodenal arcade and rupture of small arterial branches. Successful pseudoaneurysm occlusion was achieved through arterial embolization. Published by Elsevier Inc.

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.

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.

Clonal Architecture of Secondary Acute Myeloid Leukemia

PubMed Central

Walter, Matthew J.; Shen, Dong; Ding, Li; Shao, Jin; Koboldt, Daniel C.; Chen, Ken; Larson, David E.; McLellan, Michael D.; Dooling, David; Abbott, Rachel; Fulton, Robert; Magrini, Vincent; Schmidt, Heather; Kalicki-Veizer, Joelle; O’Laughlin, Michelle; Fan, Xian; Grillot, Marcus; Witowski, Sarah; Heath, Sharon; Frater, John L.; Eades, William; Tomasson, Michael; Westervelt, Peter; DiPersio, John F.; Link, Daniel C.; Mardis, Elaine R.; Ley, Timothy J.; Wilson, Richard K.; Graubert, Timothy A.

2012-01-01

BACKGROUND The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.) PMID:22417201

Dissociative semantic breakdown in Alzheimer's disease: evidence from multiple category fluency test.

PubMed

Ting, Simon Kang Seng; Hameed, Shahul; Earnest, Arul; Tan, Eng-King

2013-07-01

Category-specific semantic dissociation particularly in terms of biological and non-biological dichotomy has been described in Alzheimer's disease (AD). We re-examine above finding by performing multiple superordinate category verbal fluency test in AD patients. We analyze the baseline neuropsychological assessment performance of food and animal fluency test of AD patients from a tertiary hospital that collected prospectively over 5 years period and correlation was calculated by Kappa test. The analysis is stratified according to literacy level (primary: 0-6 years education and secondary: >6 years education) and disease severity (MMSE score: mild 19-24, moderate 13-18 and severe <13). A total of 296 AD patients were analyzed and only fair to moderate agreement between food and animal category fluency test was found especially in the mild AD cases (primary: kappa 0.42; secondary: kappa 0.40). Kappa agreement level increases when disease progress especially in the secondary education group. Food category, which is a more relevant semantic knowledge to Singapore population, is generally more affected. Higher educated subjects appeared to have less semantic dissociation effect when disease progress. Despite less primed in daily life, biological category of semantic knowledge appears to be affected less during AD process in highly urbanized Singapore society. Brain appears to have special protective mechanism towards living things. However, education level seems have a modulation effect towards the biological protective mechanism. Copyright © 2012 Elsevier B.V. All rights reserved.

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.

Construct validity and frequency of euphoria sclerotica in multiple sclerosis.

PubMed

Fishman, Inna; Benedict, Ralph H B; Bakshi, Rohit; Priore, Roger; Weinstock-Guttman, Bianca

2004-01-01

Using the Neuropsychiatric Inventory (NPI), we studied euphoria and other behavioral changes in 75 consecutive, unselected multiple sclerosis (MS) patients and 25 healthy controls. We also assessed disease duration, clinical course, physical disability, personality, depression, insight, cognition, and caregiver distress. Factor analysis identified a cluster of symptoms--labeled euphoria/disinhibition--similar to the euphoria sclerotica syndrome originally described by Charcot and others. The euphoria/disinhibition factor score was elevated in 9% of patients and associated with secondary-progressive course, low agreeableness, poor insight, impaired cognition, and high caregiver distress. Thus, we used the NPI to validate the euphoria syndrome in multiple sclerosis (MS) and determined its frequency, and its neurological and psychological correlates.

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.

Cerebrospinal fluid ATP metabolites in multiple sclerosis.

PubMed

Lazzarino, G; Amorini, A M; Eikelenboom, M J; Killestein, J; Belli, A; Di Pietro, V; Tavazzi, B; Barkhof, F; Polman, C H; Uitdehaag, B M J; Petzold, A

2010-05-01

Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 micromol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort (r= 0.66, p= 0.001) and subgroups (relapsing-remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block.

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.

Therapeutic plasma exchange in the treatment of neuroimmunologic disorders: review of 50 cases.

PubMed

Yücesan, Canan; Arslan, Onder; Arat, Mutlu; Yücemen, Nezih; Ayyildiz, Erol; Ilhan, Osman; Mutluer, Nermin

2007-02-01

Therapeutic plasma exchange (TPE) has been used for the treatment of neurologic diseases in which autoimmunity plays a major role. We reviewed the medical records of our patients who had consecutively been treated by TPE between January 1998 and June 2000. Neurological indications included myasthenia gravis (30 patients), multiple sclerosis attack (6 patients with remitting-relapsing course and 3 patients with secondary progressive course), Guillain-Barrè syndrome (6 patients), paraproteinemic neuropathy (2 patients), and chronic inflammatory demyelinating neuropathy (CIDP), transverse myelitis due to systemic lupus erythematosus, acute disseminated encephalomyelitis in one patient each. Continuous flow cell separators were used for TPE. TPE was generally given every other day for all of the patients and one plasma volume was exchanged for each cycle. Although the patients with secondary progressive multiple sclerosis (3 patients) and paraproteinemic neuropathy (2 patients) did not show any improvement after TPE, other patients' targeted neurological deficits were improved by TPE. During the TPE procedures, no patient had any morbidity or mortality, and the complications were mild and manageable such as hypotension, hypocalcemia and mild anemia; three patients had septicemia due to the venous catheter used for TPE. TPE is an effective treatment in neurologic diseases in which autoimmunity plays an important role in pathogenesis, and it is safe when performed in experienced centers.

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

"I think I use them, but I'm not sure what each one is called": Integration of multiple literacies in secondary social studies and science classes

NASA Astrophysics Data System (ADS)

Lickteig, Amanda D.

In the past, literacy was viewed solely as the basic, functional skills of reading and writing. However, with the New London Group's (1996) proposal of multiliteracies and the more recent push for a plurality of literacies (NCTE, 2011), teachers have been urged to expand their definitions of literacy. This qualitative study explores how secondary-level social studies and science teachers perceive literacies and identifies their instructional literacies practices. Data were collected through a pre- and post-questionnaire, three focus group sessions, classroom observations, field notes, and artifacts. This study solicited nearly one hundred secondary social studies and science teachers from three Midwestern school districts. Eight educators (four social studies and four science) participated in the study that took place in the spring of 2015. Furthermore, a generous grant from a local chapter of Phi Delta Kappa partially funded this research. After applying initial and holistic codes to the data, nine themes emerged: conventional, progressive, hesitant/emerging, collaborate, calibrate, perform, practice, interdisciplinary, and intradisciplinary. The nine themes were further classified by how they appeared in the data: dispositional themes, behavioral themes, and bridge themes. Throughout the data analysis, contemporary genre theory guided the study (Devitt, 2004). Descriptive codes, derived from contemporary genre theory, further revealed that the situational, social, historical, and individual aspects of genre influence teachers' pedagogical practices related to multiple literacies across disciplines. Therefore, the ways in which teachers perceived multiple literacies and implemented them into classroom instruction are multifaceted and vary depending on grade level, content area, and teaching location. However, teachers' dispositions regarding literacy move beyond a traditional mindset of functional reading and writing as they engage in professional learning opportunities and collaborate within and across disciplines and grade levels. This study provides secondary educators insight into the prominence of multiple literacies present across content areas while also revealing the teaching methods and instructional strategies that foster multiple literacies.

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 effect of growth hormone replacement in patients with hypopituitarism on pituitary tumor recurrence, secondary cancer, and stroke.

PubMed

Jasim, Sina; Alahdab, Fares; Ahmed, Ahmed T; Tamhane, Shrikant U; Sharma, Anu; Donegan, Diane; Nippoldt, Todd B; Murad, M Hassan

2017-05-01

Growth hormone replacement therapy has benefits for patients with hypopituitarism. The safety profile in regard to tumor recurrence or progression, development of secondary malignancies, or cerebrovascular stroke is still an area of debate. A comprehensive search of multiple databases-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August 2015. Eligible studies that evaluated long-term adverse events in adult patients with hypopituitarism treated with growth hormone replacement therapy and reported development of pituitary tumor recurrence or progression, secondary malignancies, or cerebrovascular stroke were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias. Random-effects meta-analysis was used to pool relative risks and 95 % confidence intervals. We included 15 studies (published 1995-2015) that reported on 46,148 patients. Compared to non-replacement, growth hormone replacement therapy in adults with hypopituitarism was not associated with statistically significant change in pituitary tumor progression or recurrence (relative risk, 0.77; 95 % confidence interval, 0.53-1.13) or development of secondary malignancy (relative risk, 0.99; 95 % confidence interval, 0.70-1.39). In two retrospective studies, there was higher risk of stroke in patients who did not receive replacement (relative risk, 2.07; 95 % confidence interval, 1.51-2.83). The quality of evidence is low due to study limitations and imprecision. This systematic review and meta-analysis supports the overall safety of growth hormone therapeutic use in adults with hypopituitarism with no clear evidence of increased risk of pituitary tumor recurrence, malignancy, or stroke.

Necrotizing fasciitis secondary to enterocutaneous fistula: three case reports.

PubMed

Gu, Guo-Li; Wang, Lin; Wei, Xue-Ming; Li, Ming; Zhang, Jie

2014-06-28

Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, and potentially fatal infection of the superficial fascia and subcutaneous tissue. NF caused by an enterocutaneous fistula has special clinical characters compared with other types of NF. NF caused by enterocutaneous fistula may have more rapid progress and more severe consequences because of multiple germs infection and corrosion by digestive juices. We treated three cases of NF caused by postoperative enterocutaneous fistula since Jan 2007. We followed empirically the principle of eliminating anaerobic conditions of infection, bypassing or draining digestive juice from the fistula and changing dressings with moist exposed burn therapy impregnated with zinc/silver acetate. These three cases were eventually cured by debridement, antibiotics and wound management.

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.

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.

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.

A learning progression based teaching module on the causes of seasons

NASA Astrophysics Data System (ADS)

Galano, S.

2016-03-01

In this paper, we report about designing and validating a teaching learning module based on a learning progression and focused on the causes of seasons. An initial learning progression about the Celestial Motion big idea -causes of seasons, lunar and solar eclipse and Moon phases- was developed and validated. Existing curricula, research studies on alternative conceptions about these phenomena, and students' answers to an open questionnaire were the starting point to develop initial learning progressions; then, a two-tier multiple-choice questionnaire was designed to validate and improve it. The questionnaire was submitted to about 300 secondary-school students whose answers were used to revise the hypothesized learning progressions. This improved version of the learning progression was used to design a module focused on the causes of seasons in which students were engaged in quantitative measurements with a photovoltaic panel to explain changes of the Sun rays' flow on the Earth's surface over the year. The efficacy of our module in improving students' understanding of the phenomenon of the seasons was tested using our questionnaire as pre- and post-test.

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.

A discrete-choice experiment to determine patient preferences for injectable multiple sclerosis treatments in Germany.

PubMed

Poulos, Christine; Kinter, Elizabeth; Yang, Jui-Chen; Bridges, John F P; Posner, Joshua; Gleißner, Erika; Mühlbacher, Axel; Kieseier, Bernd

2016-03-01

The aim of this study was to assess the relative importance of features of a hypothetical injectable disease-modifying treatment for patients with multiple sclerosis using a discrete-choice experiment. German residents at least 18 years of age with a self-reported physician diagnosis of multiple sclerosis completed a 25-30 minute online discrete-choice experiment. Patients were asked to choose one of two hypothetical injectable treatments for multiple sclerosis, defined by different levels of six attributes (disability progression, the number of relapses in the next 4 years, injection time, frequency of injections, presence of flu-like symptoms, and presence of injection-site reactions). The data were analyzed using a random-parameters logit model. Of 202 adults who completed the survey, results from 189 were used in the analysis. Approximately 50% of all patients reported a diagnosis of relapsing-remitting multiple sclerosis, and 31% reported secondary progressive multiple sclerosis. Approximately 71% of patients had current or prior experience with injectable multiple sclerosis medication. Approximately 53% had experienced flu-like symptoms caused by their medication, and 47% had experienced mild injection-site reactions. At least one significant difference was seen between levels in all attributes, except injection time. The greatest change in relative importance between levels of an attribute was years until symptoms get worse from 1 to 4 years. The magnitude of this difference was about twice that of relapses in the next 4 years, frequency of injections, and flu-like symptoms. Most attributes examined in this experiment had an influence on patient preference. Patients placed a significant value on improvements in the frequency of dosing and disability progression. Results suggest that changes in injection frequency can be as important as changes in efficacy and safety attributes. Understanding which attributes of injectable therapies influence patient preference could potentially improve outcomes and adherence in patients with multiple sclerosis.

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

Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity.

PubMed

Alves, Gilberto Sousa; Oertel Knöchel, Viola; Knöchel, Christian; Carvalho, André Férrer; Pantel, Johannes; Engelhardt, Eliasz; Laks, Jerson

2015-01-01

Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD) and may reflect primary or secondary circuitry degeneration (i.e., due to cortical atrophy). The interpretation of diffusion tensor imaging (DTI) eigenvectors, known as multiple indices, may provide new insights into the main pathological models supporting primary or secondary patterns of WM disruption in AD, the retrogenesis, and Wallerian degeneration models, respectively. The aim of this review is to analyze the current literature on the contribution of DTI multiple indices to the understanding of AD neuropathology, taking the retrogenesis model as a reference for discussion. A systematic review using MEDLINE, EMBASE, and PUBMED was performed. Evidence suggests that AD evolves through distinct patterns of WM disruption, in which retrogenesis or, alternatively, the Wallerian degeneration may prevail. Distinct patterns of WM atrophy may be influenced by complex interactions which comprise disease status and progression, fiber localization, concurrent risk factors (i.e., vascular disease, gender), and cognitive reserve. The use of DTI multiple indices in addition to other standard multimodal methods in dementia research may help to determine the contribution of retrogenesis hypothesis to the understanding of neuropathological hallmarks that lead to AD.

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.

N-acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis.

PubMed

Trentini, Alessandro; Comabella, Manuel; Tintoré, Mar; Koel-Simmelink, Marleen J A; Killestein, Joep; Roos, Birthe; Rovira, Alex; Korth, Carsten; Ottis, Philipp; Blankenstein, Marinus A; Montalban, Xavier; Bellini, Tiziana; Teunissen, Charlotte E

2014-12-01

Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R(2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R(2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.

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.

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.

Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma

PubMed Central

Goyal, Lipika; Saha, Supriya K.; Liu, Leah Y.; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G.; Lennerz, Jochen K.; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E.; Gurski, Joseph M.; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P.; Stone, James R.; Iafrate, A. John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B.; Bardeesy, Nabeel; Zhu, Andrew X.

2017-01-01

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide development of future therapeutic strategies. PMID:28034880

Necrotizing fasciitis secondary to enterocutaneous fistula: Three case reports

PubMed Central

Gu, Guo-Li; Wang, Lin; Wei, Xue-Ming; Li, Ming; Zhang, Jie

2014-01-01

Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, and potentially fatal infection of the superficial fascia and subcutaneous tissue. NF caused by an enterocutaneous fistula has special clinical characters compared with other types of NF. NF caused by enterocutaneous fistula may have more rapid progress and more severe consequences because of multiple germs infection and corrosion by digestive juices. We treated three cases of NF caused by postoperative enterocutaneous fistula since Jan 2007. We followed empirically the principle of eliminating anaerobic conditions of infection, bypassing or draining digestive juice from the fistula and changing dressings with moist exposed burn therapy impregnated with zinc/silver acetate. These three cases were eventually cured by debridement, antibiotics and wound management. PMID:24976737

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis

PubMed Central

Solanky, Bhavana S.; Muhlert, Nils; Tur, Carmen; Edden, Richard A. E.; Wheeler-Kingshott, Claudia A. M.; Miller, David H.; Thompson, Alan J.; Ciccarelli, Olga

2015-01-01

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = −0.403 mM, 95% confidence intervals −0.792, −0.014, P = 0.043) and sensorimotor cortex (adjusted difference = −0.385 mM, 95% confidence intervals −0.667, −0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted −10.86 (95% confidence intervals −16.786 to −4.482) decrease in grip strength (kg force) (P < 0.001) and −8.74 (95% confidence intervals −13.943 to −3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis. See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article. PMID:26304151

Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study.

PubMed

Kalff, Anna; Kennedy, Nola; Smiley, Angela; Prince, H Miles; Roberts, Andrew W; Bradstock, Kenneth; De Abreu Lourenço, Richard; Frampton, Chris; Spencer, Andrew

2014-12-01

We previously showed that consolidation therapy with thalidomide and prednisolone improved progression-free and overall survival in patients with multiple myeloma who had undergone autologous stem-cell transplantation. We aimed to assess whether these survival advantages were durable at 5 years. The ALLG MM6 trial was a multicentre, open-label, randomised phase 3 trial done between Jan 13, 2002, and March 15, 2005, at 29 sites in Australia and New Zealand. Patients with newly diagnosed multiple myeloma were randomly assigned (1:1), via computer-generated randomisation charts, to receive indefinite prednisolone maintenance alone (control group) or in combination with 12 months of thalidomide consolidation (thalidomide group) after autologous stem-cell transplantation. Randomisation was stratified by treating centre and pre-transplantation concentrations of β2 microglobulin. Patients and treating physicians were not masked to treatment allocation. Primary endpoints were progression-free survival and overall survival. Analysis was by intention to treat. Secondary endpoints were overall response to salvage therapy, incidence of second primary malignancy incidence, and cost-effectiveness. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12607000382471. We randomly assigned 269 patients to the thalidomide (n=114) or control group (n=129). After a median follow-up of 5·4 years (IQR 3·1-7·2), estimated 5-year progression-free survival was 27% (95% CI 23-32) in the thalidomide group and 15% (11-18) in the control group (hazard ratio [HR] 0·16, 95% CI 0·044-0·58; p=0·0054) and 5-year overall survival was 66% (95% CI 61-70) and 47% (42-51), respectively (HR 0·12, 95% CI 0·028-0·56; p=0·0072). There was no difference in overall response to salvage therapy, survival post-progression, or incidence of secondary malignancies between the two groups. Incremental cost-effectiveness ratio was AUS$26 996 per mean life-year gained. Consolidation therapy with thalidomide and prednisolone after autologous stem-cell transplantaion is an acceptable therapeutic approach when alternative drugs are not available. Pharmion Corporation, Novartis Pharmaceuticals, Amgen Australia, The Merrin Foundation, and Alfred Health. Copyright © 2014 Elsevier Ltd. All rights reserved.

Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

PubMed Central

Christensen, Jeppe Romme; Börnsen, Lars; Ratzer, Rikke; Piehl, Fredrik; Khademi, Mohsen; Olsson, Tomas; Sørensen, Per Soelberg; Sellebjerg, Finn

2013-01-01

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS. PMID:23469245

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.

Corpus callosum atrophy as a marker of clinically meaningful cognitive decline in secondary progressive multiple sclerosis. Impact on employment status.

PubMed

Papathanasiou, Athanasios; Messinis, Lambros; Zampakis, Petros; Papathanasopoulos, Panagiotis

2017-09-01

Cognitive impairment in Multiple Sclerosis (MS) is more frequent and pronounced in secondary progressive MS (SPMS). Cognitive decline is an important predictor of employment status in patients with MS. Magnetic Resonance Imaging (MRI) markers have been used to associate tissue damage with cognitive dysfunction. The aim of the study was to designate the MRI marker that predicts cognitive decline in SPMS and explore its effect on employment status. 30 SPMS patients and 30 healthy participants underwent neuropsychological assessment using the Trail Making Test (TMT) parts A and B, semantic and phonological verbal fluency task and a computerized cognitive screening battery (Central Nervous System Vital Signs). Employment status was obtained as a quality of life measure. Brain MRI was performed in all participants. We measured total lesion volume, third ventricle width, thalamic and corpus callosum atrophy. The frequency of cognitive decline for our SPMS patients was 80%. SPMS patients differed significantly from controls in all neuropsychological measures. Corpus callosum area was correlated with cognitive flexibility, processing speed, composite memory, executive functions, psychomotor speed, reaction time and phonological verbal fluency task. Processing speed and composite memory were the most sensitive markers for predicting employment status. Corpus callosum area was the most sensitive MRI marker for memory and processing speed. Corpus callosum atrophy predicts a clinically meaningful cognitive decline, affecting employment status in our SPMS patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia.

PubMed

Timms, Jessica A; Relton, Caroline L; Rankin, Judith; Strathdee, Gordon; McKay, Jill A

2016-04-01

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development.

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).

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 gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging

PubMed Central

Louapre, Céline; Govindarajan, Sindhuja T.; Giannì, Costanza; Nielsen, A. Scott; Cohen-Adad, Julien; Sloane, Jacob; Kinkel, Revere P.

2015-01-01

We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients’ normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10−10 and P < 10−7), and mean cortical T2* in controls (P < 10−5 and P < 10−6). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface. PMID:25681411

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.

The spleen in liver cirrhosis: revisiting an old enemy with novel targets.

PubMed

Li, Liang; Duan, Mubing; Chen, Weisan; Jiang, An; Li, Xiaoming; Yang, Jun; Li, Zongfang

2017-05-23

The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.

A randomized, controlled trial of the family check-up model in public secondary schools: Examining links between parent engagement and substance use progressions from early adolescence to adulthood.

PubMed

Véronneau, Marie-Hélène; Dishion, Thomas J; Connell, Arin M; Kavanagh, Kathryn

2016-06-01

Substance use in adulthood compromises work, relationships, and health. Prevention strategies in early adolescence are designed to reduce substance use and progressions to problematic use by adulthood. This report examines the long-term effects of offering Family Check-up (FCU) at multiple time points in secondary education on the progression of substance use from age 11 to 23 years. Participants (N = 998; 472 females) were randomly assigned individuals to intervention or control in Grade 6 and offered a multilevel intervention that included a classroom-based intervention (universal), the FCU (selected), and tailored family management treatment (indicated). Among intervention families, 23% engaged in the selected and indicated levels during middle school. Intention to treat analyses revealed that randomization to the FCU was associated with reduced growth in marijuana use (p < .05), but not alcohol and tobacco use. We also examined whether engagement in the voluntary FCU services moderated the effect of the intervention on substance use progressions using complier average causal effect (CACE) modeling, and found that engagement in the FCU services predicted reductions in alcohol, tobacco, and marijuana use by age 23. In comparing engagers with nonengagers: 70% versus 95% showed signs of alcohol abuse or dependence, 28% versus 61% showed signs of tobacco dependence, and 59% versus 84% showed signs of marijuana abuse or dependence. Family interventions that are embedded within public school systems can reach high-risk students and families and prevent progressions from exploration to problematic substance use through early adulthood. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

[News in neurology 2013].

PubMed

Spatola, Marianna; Rossetti, Andrea O; Michel, Patrick; Kuntzer, Thierry; Benninger, David; Nater, Bernard; Démonet, Jean-François; Schluep, Myriam; Du Pasquier, Renaud A; Vingerhoets, François

2014-01-15

In 2013, perampanel is approved as an add-on treatment for generalised and focal seizures in pharmaco-resistant epilepsy. New anticoagulants are superior to antivitamin K in stroke secondary prevention in case of atrial fibrillation. DBS remains a valid therapeutic option for advanced Parkinson's disease. Intranasal ketamine seems to reduce the intensity of severe migraine aura. High concentrations of topic capsaicin improve post-herpetic neuralgia. In Alzheimer's disease, statins might deteriorate cognitive functions. Oral immuno-modifing treatments for relapsing remitting multiple sclerosis have shown to slow cerebral atrophy progression at two years.

Multiple large infected scrotal sebaceous cysts masking Fournier's gangrene in a 32-year-old man

PubMed Central

Angus, William; Mistry, Rahul; Floyd, Michael S; Machin, Derek G

2012-01-01

Extensive large sebaceous cysts on the scotum are rare and present a problem only when infected or when cosmesis is deemed unacceptable by the patient. Fournier's gangrene is an infective condition with a high death rate. We describe a case of Fournier's gangrene in a patient masked by multiple large infected scrotal sebaceous cysts. A 32-year-old man with a history of alcohol dependency, cirrhosis and multiple scrotal sebaceous cysts presented with acute scrotal pain and erythema. Necrosis of the area became evident within 12 h of his admission and an emergency surgical debridement was performed. The wound was left open to heal via secondary intention over 4 weeks without complication. Fournier's gangrene is a rapidly progressive condition and early surgical debridement is crucial to achieve satisfactory outcomes. In this case, prompt intervention allowed a large scrotal defect to heal without the need for skin grafting. PMID:22669874

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.

Tumor cell migration in complex microenvironments

PubMed Central

Polacheck, William J.; Zervantonakis, Ioannis K.; Kamm, Roger D.

2012-01-01

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable. PMID:22926411

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.

Treatment of secondary burn wound progression in contact burns-a systematic review of experimental approaches.

PubMed

Schmauss, Daniel; Rezaeian, Farid; Finck, Tom; Machens, Hans-Guenther; Wettstein, Reto; Harder, Yves

2015-01-01

After a burn injury, superficial partial-thickness burn wounds may progress to deep partial-thickness or full-thickness burn wounds, if kept untreated. This phenomenon is called secondary burn wound progression or conversion. Burn wound depth is an important determinant of patient morbidity and mortality. Therefore, reduction or even the prevention of secondary burn wound progression is one goal of the acute care of burned patients. The objective of this study was to review preclinical approaches evaluating therapies to reduce burn wound progression. A systematic review of experimental approaches in animals that aim at reducing or preventing secondary burn wound progression was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines. The selected references consist of all the peer-reviewed studies performed in vivo in animals and review articles published in English, German, Italian, Spanish, or French language relevant to the topic of secondary burn wound progression. We searched MEDLINE, Cochrane Library, and Google Scholar including all the articles published from the beginning of notations to the present. The search was conducted between May 3, 2012 and December 26, 2013. We included 29 experimental studies in this review, investigating agents that maintain or increase local perfusion conditions, as well as agents that exhibit an anti-coagulatory, an anti-inflammatory, or an anti-apoptotic property. Warm water, simvastatin, EPO, or cerium nitrate may represent particularly promising approaches for the translation into clinical use in the near future. This review demonstrates promising experimental approaches that might reduce secondary burn wound progression. Nevertheless, a translation into clinical application needs to confirm the results compiled in experimental animal studies.

Experimental Investigation of Secondary Flow Structures Downstream of a Model Type IV Stent Failure in a 180° Curved Artery Test Section.

PubMed

Bulusu, Kartik V; Plesniak, Michael W

2016-07-19

The arterial network in the human vasculature comprises of ubiquitously present blood vessels with complex geometries (branches, curvatures and tortuosity). Secondary flow structures are vortical flow patterns that occur in curved arteries due to the combined action of centrifugal forces, adverse pressure gradients and inflow characteristics. Such flow morphologies are greatly affected by pulsatility and multiple harmonics of physiological inflow conditions and vary greatly in size-strength-shape characteristics compared to non-physiological (steady and oscillatory) flows (1 - 7). Secondary flow structures may ultimately influence the wall shear stress and exposure time of blood-borne particles toward progression of atherosclerosis, restenosis, sensitization of platelets and thrombosis (4 - 6, 8 - 13). Therefore, the ability to detect and characterize these structures under laboratory-controlled conditions is precursor to further clinical investigations. A common surgical treatment to atherosclerosis is stent implantation, to open up stenosed arteries for unobstructed blood flow. But the concomitant flow perturbations due to stent installations result in multi-scale secondary flow morphologies (4 - 6). Progressively higher order complexities such as asymmetry and loss in coherence can be induced by ensuing stent failures vis-à-vis those under unperturbed flows (5). These stent failures have been classified as "Types I-to-IV" based on failure considerations and clinical severity (14). This study presents a protocol for the experimental investigation of the complex secondary flow structures due to complete transverse stent fracture and linear displacement of fractured parts ("Type IV") in a curved artery model. The experimental method involves the implementation of particle image velocimetry (2C-2D PIV) techniques with an archetypal carotid artery inflow waveform, a refractive index matched blood-analog working fluid for phase-averaged measurements (15 - 18). Quantitative identification of secondary flow structures was achieved using concepts of flow physics, critical point theory and a novel wavelet transform algorithm applied to experimental PIV data (5, 6, 19 - 26).

Collaboration between a human group and artificial intelligence can improve prediction of multiple sclerosis course: a proof-of-principle study

PubMed Central

Ferraldeschi, Michela; Salvetti, Marco; Zaccaria, Andrea; Crisanti, Andrea; Grassi, Francesca

2017-01-01

Background: Multiple sclerosis has an extremely variable natural course. In most patients, disease starts with a relapsing-remitting (RR) phase, which proceeds to a secondary progressive (SP) form. The duration of the RR phase is hard to predict, and to date predictions on the rate of disease progression remain suboptimal. This limits the opportunity to tailor therapy on an individual patient's prognosis, in spite of the choice of several therapeutic options. Approaches to improve clinical decisions, such as collective intelligence of human groups and machine learning algorithms are widely investigated. Methods: Medical students and a machine learning algorithm predicted the course of disease on the basis of randomly chosen clinical records of patients that attended at the Multiple Sclerosis service of Sant'Andrea hospital in Rome. Results: A significant improvement of predictive ability was obtained when predictions were combined with a weight that depends on the consistence of human (or algorithm) forecasts on a given clinical record. Conclusions: In this work we present proof-of-principle that human-machine hybrid predictions yield better prognoses than machine learning algorithms or groups of humans alone. To strengthen this preliminary result, we propose a crowdsourcing initiative to collect prognoses by physicians on an expanded set of patients. PMID:29904574

Collaboration between a human group and artificial intelligence can improve prediction of multiple sclerosis course: a proof-of-principle study.

PubMed

Tacchella, Andrea; Romano, Silvia; Ferraldeschi, Michela; Salvetti, Marco; Zaccaria, Andrea; Crisanti, Andrea; Grassi, Francesca

2017-01-01

Background: Multiple sclerosis has an extremely variable natural course. In most patients, disease starts with a relapsing-remitting (RR) phase, which proceeds to a secondary progressive (SP) form. The duration of the RR phase is hard to predict, and to date predictions on the rate of disease progression remain suboptimal. This limits the opportunity to tailor therapy on an individual patient's prognosis, in spite of the choice of several therapeutic options. Approaches to improve clinical decisions, such as collective intelligence of human groups and machine learning algorithms are widely investigated. Methods: Medical students and a machine learning algorithm predicted the course of disease on the basis of randomly chosen clinical records of patients that attended at the Multiple Sclerosis service of Sant'Andrea hospital in Rome. Results: A significant improvement of predictive ability was obtained when predictions were combined with a weight that depends on the consistence of human (or algorithm) forecasts on a given clinical record. Conclusions: In this work we present proof-of-principle that human-machine hybrid predictions yield better prognoses than machine learning algorithms or groups of humans alone. To strengthen this preliminary result, we propose a crowdsourcing initiative to collect prognoses by physicians on an expanded set of patients.

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.

A Parallel Algorithm for Contact in a Finite Element Hydrocode

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

Pierce, Timothy G.

A parallel algorithm is developed for contact/impact of multiple three dimensional bodies undergoing large deformation. As time progresses the relative positions of contact between the multiple bodies changes as collision and sliding occurs. The parallel algorithm is capable of tracking these changes and enforcing an impenetrability constraint and momentum transfer across the surfaces in contact. Portions of the various surfaces of the bodies are assigned to the processors of a distributed-memory parallel machine in an arbitrary fashion, known as the primary decomposition. A secondary, dynamic decomposition is utilized to bring opposing sections of the contacting surfaces together on the samemore » processors, so that opposing forces may be balanced and the resultant deformation of the bodies calculated. The secondary decomposition is accomplished and updated using only local communication with a limited subset of neighbor processors. Each processor represents both a domain of the primary decomposition and a domain of the secondary, or contact, decomposition. Thus each processor has four sets of neighbor processors: (a) those processors which represent regions adjacent to it in the primary decomposition, (b) those processors which represent regions adjacent to it in the contact decomposition, (c) those processors which send it the data from which it constructs its contact domain, and (d) those processors to which it sends its primary domain data, from which they construct their contact domains. The latter three of these neighbor sets change dynamically as the simulation progresses. By constraining all communication to these sets of neighbors, all global communication, with its attendant nonscalable performance, is avoided. A set of tests are provided to measure the degree of scalability achieved by this algorithm on up to 1024 processors. Issues related to the operating system of the test platform which lead to some degradation of the results are analyzed. This algorithm has been implemented as the contact capability of the ALE3D multiphysics code, and is currently in production use.« less

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

DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia

PubMed Central

Timms, Jessica A; Relton, Caroline L; Rankin, Judith; Strathdee, Gordon; McKay, Jill A

2016-01-01

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple ‘hits’ are required for disease progression; an initial genetic abnormality followed by additional secondary ‘hits’. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development. PMID:27035209

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.

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

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.

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.

PubMed

Cawley, Niamh; Solanky, Bhavana S; Muhlert, Nils; Tur, Carmen; Edden, Richard A E; Wheeler-Kingshott, Claudia A M; Miller, David H; Thompson, Alan J; Ciccarelli, Olga

2015-09-01

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

Fourier transform power spectrum is a potential measure of tissue alignment in standard MRI: A multiple sclerosis study.

PubMed

Sharma, Shrushrita; Zhang, Yunyan

2017-01-01

Loss of tissue coherency in brain white matter is found in many neurological diseases such as multiple sclerosis (MS). While several approaches have been proposed to evaluate white matter coherency including fractional anisotropy and fiber tracking in diffusion-weighted imaging, few are available for standard magnetic resonance imaging (MRI). Here we present an image post-processing method for this purpose based on Fourier transform (FT) power spectrum. T2-weighted images were collected from 19 patients (10 relapsing-remitting and 9 secondary progressive MS) and 19 age- and gender-matched controls. Image processing steps included: computation, normalization, and thresholding of FT power spectrum; determination of tissue alignment profile and dominant alignment direction; and calculation of alignment complexity using a new measure named angular entropy. To test the validity of this method, we used a highly organized brain white matter structure, corpus callosum. Six regions of interest were examined from the left, central and right aspects of both genu and splenium. We found that the dominant orientation of each ROI derived from our method was significantly correlated with the predicted directions based on anatomy. There was greater angular entropy in patients than controls, and a trend to be greater in secondary progressive MS patients. These findings suggest that it is possible to detect tissue alignment and anisotropy using traditional MRI, which are routinely acquired in clinical practice. Analysis of FT power spectrum may become a new approach for advancing the evaluation and management of patients with MS and similar disorders. Further confirmation is warranted.

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.

Secondary pigmentary glaucoma in patients with underlying primary pigment dispersion syndrome.

PubMed

Sivaraman, Kavitha R; Patel, Chirag G; Vajaranant, Thasarat S; Aref, Ahmad A

2013-01-01

Primary pigment dispersion syndrome (PPDS) is a bilateral condition that occurs in anatomically predisposed individuals. PPDS may evolve into pigmentary glaucoma, but it is difficult to predict which patients will progress. Secondary pigment dispersion is more often unilateral and acquired as a result of surgery, trauma, or intraocular tumor, but can likewise lead to pigmentary glaucoma. We report two cases of patients with bilateral PPDS who developed secondary pigment dispersion and pigmentary glaucoma in one eye. Patients with PPDS who acquire a secondary mechanism of pigment dispersion may be at an increased risk of progression to pigmentary glaucoma, presumably due to an increased burden of liberated pigment. In addition to regular surveillance for progression to glaucoma from PPDS, secondary causes of pigmentary dispersion in these eyes should be considered when patients present with grossly asymmetric findings. When secondary pigment dispersion is identified in eyes with PPDS, we recommend prompt intervention to alleviate the cause of secondary pigment dispersion and/or aggressive control of intraocular pressure to limit glaucomatous damage.

Secondary pigmentary glaucoma in patients with underlying primary pigment dispersion syndrome

PubMed Central

Sivaraman, Kavitha R; Patel, Chirag G; Vajaranant, Thasarat S; Aref, Ahmad A

2013-01-01

Primary pigment dispersion syndrome (PPDS) is a bilateral condition that occurs in anatomically predisposed individuals. PPDS may evolve into pigmentary glaucoma, but it is difficult to predict which patients will progress. Secondary pigment dispersion is more often unilateral and acquired as a result of surgery, trauma, or intraocular tumor, but can likewise lead to pigmentary glaucoma. We report two cases of patients with bilateral PPDS who developed secondary pigment dispersion and pigmentary glaucoma in one eye. Patients with PPDS who acquire a secondary mechanism of pigment dispersion may be at an increased risk of progression to pigmentary glaucoma, presumably due to an increased burden of liberated pigment. In addition to regular surveillance for progression to glaucoma from PPDS, secondary causes of pigmentary dispersion in these eyes should be considered when patients present with grossly asymmetric findings. When secondary pigment dispersion is identified in eyes with PPDS, we recommend prompt intervention to alleviate the cause of secondary pigment dispersion and/or aggressive control of intraocular pressure to limit glaucomatous damage. PMID:23569351

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.

Group A streptococcal toxic shock syndrome secondary to necrotizing pelvic inflammatory disease in a postmenopausal woman.

PubMed

Paulson, Qiwei; Douglass, Elizabeth; Moreno, Alejandro; Aydelotte, Jayson

2016-01-01

Group A β-hemolytic streptococcus (GAS) is well known to cause upper respiratory tract or cutaneous infections, but some more virulent species of GAS can lead to a rapidly progressive life threatening soft tissue necrotizing infection and streptococcal toxic shock syndrome (STSS). In the modern era, GAS infections within the female reproductive tract leading to STSS are unusual and are often the result of retained products of conception or intrauterine devices. This report describes a case of GAS necrotizing pelvic infection in a previously healthy menopausal woman with no obvious portal of entry. Her clinical course rapidly progressed to septic shock and multiorgan failure. She required multiple surgeries in addition to targeted antimicrobials and aggressive management of shock and organ failures. After a prolonged hospital stay, she had a full recovery.

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.

Factors associated with clinically significant increased walking time in multiple sclerosis: results of a survival analysis of short-term follow-up data from a clinical database.

PubMed

Miller, Deborah M; Thompson, Nicolas R; Cohen, Jeffrey A; Fox, Robert J; Hartman, Jen; Schwetz, Kathleen; Conway, Devon S; Rudick, Richard A

2015-04-01

Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. The objective of this paper is to study the prediction of walking impairment in MS. We retrieved data for all MS patients at our center (2008-2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing-remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change. © The Author(s), 2014.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort

PubMed Central

Zang, R Y; Harter, P; Chi, D S; Sehouli, J; Jiang, R; Tropé, C G; Ayhan, A; Cormio, G; Xing, Y; Wollschlaeger, K M; Braicu, E I; Rabbitt, C A; Oksefjell, H; Tian, W J; Fotopoulou, C; Pfisterer, J; du Bois, A; Berek, J S

2011-01-01

Background: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. Methods: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. Results: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (⩽23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. Conclusion: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer. PMID:21878937

"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."

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.

Incorporating multiple secondary targets into learning trials for individuals with autism spectrum disorder.

PubMed

Nottingham, Casey L; Vladescu, Jason C; Kodak, Tiffany; Kisamore, April N

2017-07-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary target was presented in the consequence of each trial, and (d) no additional targets were presented trials. The participants acquired the majority of secondary targets. Presenting one or multiple secondary targets per trial, regardless of the location of these secondary targets, increased the efficiency of instruction in comparison to a condition with no secondary target. © 2017 Society for the Experimental Analysis of Behavior.

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

PubMed

Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

2012-07-01

Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.

Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function.

PubMed

Ontaneda, Daniel; Thompson, Alan J; Fox, Robert J; Cohen, Jeffrey A

2017-04-01

Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute transfusion-related abdominal injury in trauma patients: a case report.

PubMed

Michel, P; Wähnert, D; Freistühler, M; Laukoetter, M G; Rehberg, S; Raschke, M J; Garcia, P

2016-10-19

Secondary abdominal compartment syndrome is well known as a life-threatening complication in critically ill patients in an intensive care unit. Massive crystalloid fluid resuscitation has been identified as the most important risk factor. The time interval from hospital admittance to the development of manifest abdominal compartment syndrome is usually greater than 24 hours. In the absence of any direct abdominal trauma, we observed a rapidly evolving secondary abdominal compartment syndrome shortly after hospital admittance associated with massive transfusion of blood products and only moderate crystalloid resuscitation. We report the case of an acute secondary abdominal compartment syndrome developing within 3 to 4 hours in a 74-year-old polytraumatized white woman. Although multiple fractures of her extremities and a B-type pelvic ring fracture were diagnosed by a full body computed tomography scan, no intra-abdominal injury could be detected. Hemorrhagic shock with a drop in her hemoglobin level to 5.7 g/dl was treated by massive transfusion of blood products and high doses of catecholamines. Shortly afterwards, her pulmonary gas exchange progressively deteriorated and mechanical ventilation became almost impossible with peak airway pressures of up to 60 cmH 2 O. Her abdomen appeared rigid and tense accompanied by a progressive hemodynamic decompensation necessitating mechanic cardiopulmonary resuscitation. Although preoperative computed tomography scans showed no signs of intra-abdominal fluid, a decompressive laparotomy under cardiopulmonary resuscitation conditions was performed and 2 liters of ascites-like fluid disgorged. Her hemodynamics and pulmonary ventilation improved immediately. This case report describes for the first time acute secondary abdominal compartment syndrome in a trauma patient, evolving in a very short time period. We hypothesize that the massive transfusion of blood products along with high doses of catecholamines triggered the acute development of abdominal compartment syndrome. Trauma teams need to consider a rapidly developing secondary abdominal compartment syndrome to be a potential cause of hemodynamic decompensation not only in the later phase of treatment but also in the emergency phase of treatment.

Progress Monitoring the Effects of Daily Report Cards across Elementary and Secondary Settings Using Direct Behavior Rating: Single Item Scales

ERIC Educational Resources Information Center

Miller, Faith G.; Crovello, Nicholas J.; Chafouleas, Sandra M.

2017-01-01

Direct Behavior Rating-Single Item Scales (DBR-SIS) have been advanced as a promising, systematic, behavioral, progress-monitoring method that is flexible, efficient, and defensible. This study aimed to extend existing literature on the use of DBR-SIS in elementary and secondary settings, and to examine methods of monitoring student progress in…

Multiple recurrent ischaemic strokes in a patient with cancer: is there a role for the initiation of anticoagulation therapy for secondary stroke prevention?

PubMed Central

Suero-Abreu, Giselle Alexandra; Cheng, Jia Zhen; Then, Ryna Karina

2017-01-01

A 52-year-old woman with a medical history of cervical and thyroid cancer, hypertension, dyslipidaemia, uncontrolled diabetes and heavy smoking was diagnosed with a new metastatic cholangiocarcinoma. While undergoing palliative chemotherapy, she developed dysarthria and left-sided weakness. Imaging studies showed multiple bilateral ischaemic strokes. On hospital days 2 and 5, she developed worsening neurological symptoms and imaging studies revealed new areas of ischaemia on respective days. Subsequent workup did not revealed a clear aetiology for the multiple ischaemic events and hypercoagulability studies were only significant for a mildly elevated serum D-dimer level. Although guidelines are unclear, full-dose anticoagulation with low molecular weight heparin was initiated given her high risk of stroke recurrence. She was discharged to acute rehabilitation but, within a month, she experienced complications of her malignant disease progression and a new pulmonary thromboembolism. The patient died soon after being discharged home with hospice care. PMID:28578306

Progress through High School: A Study of Senior Secondary Schooling in New South Wales. ACER Research Monograph No. 43.

ERIC Educational Resources Information Center

Ainley, John; Sheret, Michael

This book provides an overview of a 4-year longitudinal study of senior secondary schooling in the government high schools of New South Wales, Australia. The study followed the progress from year 9 to year 12 of 3,000 students from 22 government secondary schools in 2 metropolitan and 2 nonmetropolitan regions. The book is divided into 10…

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

PubMed

Facon, Thierry; Dimopoulos, Meletios A; Dispenzieri, Angela; Catalano, John V; Belch, Andrew; Cavo, Michele; Pinto, Antonello; Weisel, Katja; Ludwig, Heinz; Bahlis, Nizar J; Banos, Anne; Tiab, Mourad; Delforge, Michel; Cavenagh, Jamie D; Geraldes, Catarina; Lee, Je-Jung; Chen, Christine; Oriol, Albert; De La Rubia, Javier; White, Darrell; Binder, Daniel; Lu, Jin; Anderson, Kenneth C; Moreau, Philippe; Attal, Michel; Perrot, Aurore; Arnulf, Bertrand; Qiu, Lugui; Roussel, Murielle; Boyle, Eileen; Manier, Salomon; Mohty, Mohamad; Avet-Loiseau, Herve; Leleu, Xavier; Ervin-Haynes, Annette; Chen, Guang; Houck, Vanessa; Benboubker, Lotfi; Hulin, Cyrille

2018-01-18

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. © 2018 by The American Society of Hematology.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

PubMed Central

Dimopoulos, Meletios A.; Dispenzieri, Angela; Catalano, John V.; Belch, Andrew; Cavo, Michele; Pinto, Antonello; Weisel, Katja; Ludwig, Heinz; Bahlis, Nizar J.; Banos, Anne; Tiab, Mourad; Delforge, Michel; Cavenagh, Jamie D.; Geraldes, Catarina; Lee, Je-Jung; Chen, Christine; Oriol, Albert; De La Rubia, Javier; White, Darrell; Binder, Daniel; Lu, Jin; Anderson, Kenneth C.; Moreau, Philippe; Attal, Michel; Perrot, Aurore; Arnulf, Bertrand; Qiu, Lugui; Roussel, Murielle; Boyle, Eileen; Manier, Salomon; Mohty, Mohamad; Avet-Loiseau, Herve; Leleu, Xavier; Ervin-Haynes, Annette; Chen, Guang; Houck, Vanessa; Benboubker, Lotfi; Hulin, Cyrille

2018-01-01

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months’ follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. PMID:29150421

Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.

PubMed

Shimizu, Fumitaka; Tasaki, Ayako; Sano, Yasuteru; Ju, Mihua; Nishihara, Hideaki; Oishi, Mariko; Koga, Michiaki; Kawai, Motoharu; Kanda, Takashi

2014-01-01

Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients. We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.

Secondary Progressive and Relapsing Remitting Multiple Sclerosis Leads to Motor-Related Decreased Anatomical Connectivity

PubMed Central

Lyksborg, Mark; Siebner, Hartwig R.; Sørensen, Per S.; Blinkenberg, Morten; Parker, Geoff J. M.; Dogonowski, Anne-Marie; Garde, Ellen; Larsen, Rasmus; Dyrby, Tim B.

2014-01-01

Multiple sclerosis (MS) damages central white matter pathways which has considerable impact on disease-related disability. To identify disease-related alterations in anatomical connectivity, 34 patients (19 with relapsing remitting MS (RR-MS), 15 with secondary progressive MS (SP-MS) and 20 healthy subjects underwent diffusion magnetic resonance imaging (dMRI) of the brain. Based on the dMRI, anatomical connectivity mapping (ACM) yielded a voxel-based metric reflecting the connectivity shared between each individual voxel and all other brain voxels. To avoid biases caused by inter-individual brain-shape differences, they were estimated in a spatially normalized space. Voxel-based statistical analyses using ACM were compared with analyses based on the localized microstructural indices of fractional anisotropy (FA). In both RR-MS and SP-MS patients, considerable portions of the motor-related white matter revealed decreases in ACM and FA when compared with healthy subjects. Patients with SP-MS exhibited reduced ACM values relative to RR-MS in the motor-related tracts, whereas there were no consistent decreases in FA between SP-MS and RR-MS patients. Regional ACM statistics exhibited moderate correlation with clinical disability as reflected by the expanded disability status scale (EDSS). The correlation between these statistics and EDSS was either similar to or stronger than the correlation between FA statistics and the EDSS. Together, the results reveal an improved relationship between ACM, the clinical phenotype, and impairment. This highlights the potential of the ACM connectivity indices to be used as a marker which can identify disease related-alterations due to MS which may not be seen using localized microstructural indices. PMID:24748023

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.

The experience of transitioning from relapsing remitting to secondary progressive multiple sclerosis: views of patients and health professionals.

PubMed

O'Loughlin, Emer; Hourihan, Susan; Chataway, Jeremy; Playford, E Diane; Riazi, Afsane

2017-09-01

The majority of people with multiple sclerosis (pwMS) initially present with discreet periods of relapses followed by partial remission of symptoms (RRMS). Over time, most pwMS transition to secondary progressive MS (SPMS), characterized by a gradual accumulation of disability. This study aimed to explore the experiences, coping and needs associated with transitioning from RRMS to SPMS. Data were collected via semi-structured interviews with nine pwMS and seven specialist MS health professionals (HPs). Thematic analysis was used to analyze the data. Four major themes were identified: "Is this really happening?"; "Becoming a reality"; "A life of struggle"; and "Brushing oneself off and moving on." Findings suggested a process of moving from uncertainty towards confirmation of one's diagnostic label. Being reclassified with SPMS served as a turning point for many, and was accompanied by a range of cognitive, emotional and behavioral responses. The value of adequate information and support surrounding the transition, and the potential benefit of education and support for health professionals in relation to the transition were indicated. Understanding pwMS' experiences of the transition is essential if clinicians are to provide pwMS with appropriate support during the transition. Implications for Rehabilitation The timing and delivery of preparatory education for patients about the transition to SPMS should be carefully considered. Sufficient information and follow-up support following the reclassification of SPMS is crucial but sometimes lacking. The importance of sensitive communication of the reclassification of SPMS was highlighted. MS Specialist health professionals may potentially benefit from training and support around communication of the reclassification of SPMS. Given the potential negative psychological impact of the transition, the psychological wellbeing of the patients during the transition to SPMS should be monitored and responded to appropriately.

CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple Sclerosis Resistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study.

PubMed

Belogurov, Alexey; Zakharov, Konstantin; Lomakin, Yakov; Surkov, Kirill; Avtushenko, Sergey; Kruglyakov, Peter; Smirnov, Ivan; Makshakov, Gleb; Lockshin, Curtis; Gregoriadis, Gregory; Genkin, Dmitry; Gabibov, Alexander; Evdoshenko, Evgeniy

2016-10-01

Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP 46-62 , MBP 124-139 and MBP 147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.

Multiple Intelligences Profiles of Junior Secondary School Students in Indonesia

ERIC Educational Resources Information Center

Emmiyati, Nuri; Rasyid, Muhammad Amin; Rahman, M. Asfah; Arsyad, Azhar; Dirawan, Gufran Darma

2014-01-01

This study aimed to investigate the Multiple Intelligences profiles of the students at junior secondary school in Makassar. The Multiple Intelligences Inventory was used to identify the dominant intelligence among the students. The sample of this research was 302 junior secondary schools students in Makassar Indonesia who willing to participated…

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.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

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.

Placebo-controlled trial of oral laquinimod for multiple sclerosis.

PubMed

Comi, Giancarlo; Jeffery, Douglas; Kappos, Ludwig; Montalban, Xavier; Boyko, Alexey; Rocca, Maria A; Filippi, Massimo

2012-03-15

Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging. Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%). In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.).

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species.

PubMed

Challis, Gregory L; Hopwood, David A

2003-11-25

In this article we briefly review theories about the ecological roles of microbial secondary metabolites and discuss the prevalence of multiple secondary metabolite production by strains of Streptomyces, highlighting results from analysis of the recently sequenced Streptomyces coelicolor and Streptomyces avermitilis genomes. We address this question: Why is multiple secondary metabolite production in Streptomyces species so commonplace? We argue that synergy or contingency in the action of individual metabolites against biological competitors may, in some cases, be a powerful driving force for the evolution of multiple secondary metabolite production. This argument is illustrated with examples of the coproduction of synergistically acting antibiotics and contingently acting siderophores: two well-known classes of secondary metabolite. We focus, in particular, on the coproduction of beta-lactam antibiotics and beta-lactamase inhibitors, the coproduction of type A and type B streptogramins, and the coregulated production and independent uptake of structurally distinct siderophores by species of Streptomyces. Possible mechanisms for the evolution of multiple synergistic and contingent metabolite production in Streptomyces species are discussed. It is concluded that the production by Streptomyces species of two or more secondary metabolites that act synergistically or contingently against biological competitors may be far more common than has previously been recognized, and that synergy and contingency may be common driving forces for the evolution of multiple secondary metabolite production by these sessile saprophytes.

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

PubMed Central

Challis, Gregory L.; Hopwood, David A.

2003-01-01

In this article we briefly review theories about the ecological roles of microbial secondary metabolites and discuss the prevalence of multiple secondary metabolite production by strains of Streptomyces, highlighting results from analysis of the recently sequenced Streptomyces coelicolor and Streptomyces avermitilis genomes. We address this question: Why is multiple secondary metabolite production in Streptomyces species so commonplace? We argue that synergy or contingency in the action of individual metabolites against biological competitors may, in some cases, be a powerful driving force for the evolution of multiple secondary metabolite production. This argument is illustrated with examples of the coproduction of synergistically acting antibiotics and contingently acting siderophores: two well-known classes of secondary metabolite. We focus, in particular, on the coproduction of β-lactam antibiotics and β-lactamase inhibitors, the coproduction of type A and type B streptogramins, and the coregulated production and independent uptake of structurally distinct siderophores by species of Streptomyces. Possible mechanisms for the evolution of multiple synergistic and contingent metabolite production in Streptomyces species are discussed. It is concluded that the production by Streptomyces species of two or more secondary metabolites that act synergistically or contingently against biological competitors may be far more common than has previously been recognized, and that synergy and contingency may be common driving forces for the evolution of multiple secondary metabolite production by these sessile saprophytes. PMID:12970466

Analysis of secondary cytoreduction for recurrent ovarian cancer by robotics, laparoscopy and laparotomy.

PubMed

Magrina, Javier F; Cetta, Rachel L; Chang, Yu-Hui; Guevara, Gregory; Magtibay, Paul M

2013-05-01

Analysis of perioperative outcomes and survival of patients with recurrent ovarian cancer undergoing secondary cytoreduction by robotics, laparoscopy, or laparotomy. Retrospective analysis of 52 selected patients with recurrent ovarian cancer undergoing secondary cytoreduction by laparoscopy (9), laparotomy (33) or robotics (10) between January 2006 and December 2010. Comparison was made by a total of 21 factors including age, BMI, number of previous surgeries, tumor type and grade, number of procedures, and 15 types of procedures performed at secondary cytoreduction. For all patients, the mean operating time was 213.8 min, mean blood loss 657.4 ml; and mean hospital stay 7.5 days. Complete debulking was achieved in 75% of patients. Postoperative complications were noted in 36.5% of patients. Overall and progression-free survival at 3-years were 58.8% and 34.1%, respectively. Laparoscopy and robotics had reduced blood loss and hospital stay, while no differences were observed among the three groups for operating time, complications, complete debulking, and survival. Selected patients with recurrent ovarian cancer benefit from a laparoscopic or robotic secondary cytoreduction without compromising survival. Robotics and laparoscopy provide similar perioperative outcomes, and reduced blood loss and shorter hospital stay as compared to laparotomy. Laparotomy seems preferable for patients with widespread peritoneal implants, multiple sites of recurrence, and/or extensive adhesions. Copyright © 2013 Elsevier Inc. All rights reserved.

Foxi3 deficiency compromises hair follicle stem cell specification and activation

PubMed Central

Shirokova, Vera; Biggs, Leah C.; Jussila, Maria; Ohyama, Takahiro; Groves, Andrew K.; Mikkola, Marja L.

2017-01-01

The hair follicle is an ideal system to study stem cell specification and homeostasis due to its well characterized morphogenesis and stereotypic cycles of stem cell activation upon each hair cycle to produce a new hair shaft. The adult hair follicle stem cell niche consists of two distinct populations, the bulge and the more activation-prone secondary hair germ. Hair follicle stem cells are set aside during early stages of morphogenesis. This process is known to depend on the Sox9 transcription factor, but otherwise the establishment of the hair follicle stem cell niche is poorly understood. Here we show that that mutation of Foxi3, a Forkhead family transcription factor mutated in several hairless dog breeds, compromises stem cell specification. Further, loss of Foxi3 impedes hair follicle downgrowth and progression of the hair cycle. Genome-wide profiling revealed a number of downstream effectors of Foxi3 including transcription factors with a recognized function in hair follicle stem cells such as Lhx2, Runx1, and Nfatc1, suggesting that the Foxi3 mutant phenotype results from simultaneous downregulation of several stem cell signature genes. We show that Foxi3 displays a highly dynamic expression pattern during hair morphogenesis and cycling, and identify Foxi3 as a novel secondary hair germ marker. Absence of Foxi3 results in poor hair regeneration upon hair plucking, and a sparse fur phenotype in unperturbed mice that exacerbates with age, caused by impaired secondary hair germ activation leading to progressive depletion of stem cells. Thus, Foxi3 regulates multiple aspects of hair follicle development and homeostasis. PMID:26992132

The life cycles of intense cyclonic and anticyclonic circulation systems observed over oceans

NASA Technical Reports Server (NTRS)

Smith, Phillip J.

1994-01-01

The work over the past six months has focused on the October/November 1985 blocking case study noted in the last progress report. A summary of the results of this effort is contained in the attached preprint papers for the Symposium on the Life Cycles of Extratropical Cyclones. Using this case study as a model, Ph.D. student Anthony Lupo is now initiating the multiple-case diagnosis by first examining two more fall 1985 blocking episodes. In addition, two secondary efforts have been completed, as summarized in the attached M.S. thesis abstracts. Both studies, which were primarily funded by a fellowship and a teaching assistantship, complement the objectives of this study by providing diagnoses of additional cyclone cases to serve as a comparative base for the pre-blocking cyclones to be studied in the multiple-case blocking diagnosis.

Sequence to Structure (S2S): display, manipulate and interconnect RNA data from sequence to structure.

PubMed

Jossinet, Fabrice; Westhof, Eric

2005-08-01

Efficient RNA sequence manipulations (such as multiple alignments) need to be constrained by rules of RNA structure folding. The structural knowledge has increased dramatically in the last years with the accumulation of several large RNA structures similar to those of the bacterial ribosome subunits. However, no tool in the RNA community provides an easy way to link and integrate progress made at the sequence level using the available three-dimensional information. Sequence to Structure (S2S) proposes a framework in which an user can easily display, manipulate and interconnect heterogeneous RNA data, such as multiple sequence alignments, secondary and tertiary structures. S2S has been implemented using the Java language and has been developed and tested under UNIX systems, such as Linux and MacOSX. S2S is available at http://bioinformatics.org/S2S/.

Progressive subcortical calcifications secondary to venous hypertension in an intracranial dural arteriovenous fistula.

PubMed

Pascoe, Heather M; Lui, Elaine H; Mitchell, Peter; Gaillard, Frank

2017-05-01

Intracranial dural arteriovenous fistulas (dAVF) are acquired lesions, with the most commonly reported findings on CT haemorrhage or focal oedema. We describe a case of progressive subcortical calcification on CT secondary to venous hypertension from a high grade dAVF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Invisible Barriers: The Career Progress of Women Secondary School Principals in Greece

ERIC Educational Resources Information Center

Kaparou, Maria; Bush, Tony

2007-01-01

This paper examines the career progress of female principals in Greek secondary schools and the under-representation of women in management positions. Drawing on in-depth interviews with six women principals in Athens, the paper considers the factors affecting women's participation in school management. The findings demonstrate that women are…

The soil biota composition along a progressive succession of secondary vegetation in a karst area.

PubMed

Zhao, Jie; Li, Shengping; He, Xunyang; Liu, Lu; Wang, Kelin

2014-01-01

Karst ecosystems are fragile and are in many regions degraded by anthropogenic activities. Current management of degraded karst areas focuses on aboveground vegetation succession or recovery and aims at establishing a forest ecosystem. Whether progressive succession of vegetation in karst areas is accompanied by establishment of soil biota is poorly understood. In the present study, soil microbial and nematode communities, as well as soil physico-chemical properties were studied along a progressive succession of secondary vegetation (from grassland to shrubland to forest) in a karst area in southwest China. Microbial biomass, nematode density, ratio of fungal to bacterial biomass, nematode structure index, and nematode enrichment index decreased with the secondary succession in the plant community. Overall, the results indicated a pattern of declines in soil biota abundance and food web complexity that was associated with a decrease in soil pH and a decrease in soil organic carbon content with the progressive secondary succession of the plant community. Our findings suggest that soil biota amendment is necessary during karst ecosystem restoration and establishment and management of grasslands may be feasible in karst areas.

Improving progression and continuity from primary to secondary science: Pupils' reactions to bridging work

NASA Astrophysics Data System (ADS)

Braund, Martin; Hames, Vicky

2005-07-01

This article reports research from a project set up to implement ‘bridging work’ in science in England. Group interviews of 59 pupils in Year 6 (at the end of primary school) and 48 pupils in Year 7 (at beginning of secondary school) were carried out after pupils had completed bridging work. Twenty-six of this sample were the same pupils. Semi-structured interviews were carried out in groups to ascertain: their aspirations and fears concerning secondary science, their reactions to bridging work and their memories of investigations. Year 6 pupils were positive about studying science at secondary school and remained so after transfer. Pupils' reactions to bridging at both ages were very positive. Findings challenge recent critiques of bridging. The lack of progression in pupils' communication about the variables and findings from investigations suggest that the planned progression of work was not recognized by some teachers. Bridging work alone may not guarantee improved progression and continuity in science, but as part of a carefully planned and structured programme of collaboration it has merit.

Incorporating Multiple Secondary Targets into Learning Trials for Individuals with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Nottingham, Casey L.; Vladescu, Jason C.; Kodak, Tiffany; Kisamore, April N.

2017-01-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary…

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

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

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model

PubMed Central

Swift, Brenna E.; Williams, Brent A.; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A.; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

2012-01-01

Background Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. Design and Methods The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Results Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89–99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. Conclusions This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted. PMID:22271890

Symptomatic Cushing's syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report.

PubMed

Sedhom, Ramy; Hu, Sophia; Ohri, Anupam; Infantino, Dorian; Lubitz, Sara

2016-10-12

Malignant steroid cell tumors of the ovary are rare and frequently associated with hormonal abnormalities. There are no guidelines on how to treat rapidly progressive Cushing's syndrome, a medical emergency. A 67-year-old white woman presented to our hospital with rapidly developing signs and symptoms of Cushing's syndrome secondary to a steroid-secreting tumor. Her physical and biochemical manifestations of Cushing's syndrome progressed, and she was not amenable to undergoing conventional chemotherapy secondary to the debilitating effects of high cortisol. Her rapidly progressive Cushing's syndrome ultimately led to her death, despite aggressive medical management with spironolactone, ketoconazole, mitotane, and mifepristone. We report an unusual and rare case of Cushing's syndrome secondary to a malignant steroid cell tumor of the ovary. The case is highlighted to discuss the complications of rapidly progressive Cushing's syndrome, an underreported and often unrecognized endocrine emergency, and the best available evidence for treatment.

Toll-Like Receptors in Secondary Obstructive Cholangiopathy

PubMed Central

Miranda-Díaz, A. G.; Alonso-Martínez, H.; Hernández-Ojeda, J.; Arias-Carvajal, O.; Rodríguez-Carrizalez, A. D.; Román-Pintos, L. M.

2011-01-01

Secondary obstructive cholangiopathy is characterized by intra- or extrahepatic bile tract obstruction. Liver inflammation and structural alterations develop due to progressive bile stagnation. Most frequent etiologies are biliary atresia in children, and hepatolithiasis, postcholecystectomy bile duct injury, and biliary primary cirrhosis in adults, which causes chronic biliary cholangitis. Bile ectasia predisposes to multiple pathogens: viral infections in biliary atresia; Gram-positive and/or Gram-negative bacteria cholangitis found in hepatolithiasis and postcholecystectomy bile duct injury. Transmembrane toll-like receptors (TLRs) are activated by virus, bacteria, fungi, and parasite stimuli. Even though TLR-2 and TLR-4 are the most studied receptors related to liver infectious diseases, other TLRs play an important role in response to microorganism damage. Acquired immune response is not vertically transmitted and reflects the infectious diseases history of individuals; in contrast, innate immunity is based on antigen recognition by specific receptors designated as pattern recognition receptors and is transmitted vertically through the germ cells. Understanding the mechanisms for bile duct inflammation is essential for the future development of therapeutic alternatives in order to avoid immune-mediated destruction on secondary obstructive cholangiopathy. The role of TLRs in biliary atresia, hepatolithiasis, bile duct injury, and primary biliary cirrhosis is described in this paper. PMID:22114589

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.

Progressive Atelectasis Secondary to GSW to Airway

DTIC Science & Technology

2009-05-01

compression, cicatrization , adhesion and Progressive Atelectasis Secondary to GSW Military Medicine Radiology Corner, Volume 174 May 2009...in retraction or entire collapse of lung lobes. The next main cause of atelectasis, cicatrization , is also produced by the interaction of...mechanical forces. In cicatrization atelectasis, pulmonary fibrosis stiffens the alveoli, causing a decrease in compliance and alveolar volume

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

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.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

PubMed

Kim, Gloria; Chu, Renxin; Yousuf, Fawad; Tauhid, Shahamat; Stazzone, Lynn; Houtchens, Maria K; Stankiewicz, James M; Severson, Christopher; Kimbrough, Dorlan; Quintana, Francisco J; Chitnis, Tanuja; Weiner, Howard L; Healy, Brian C; Bakshi, Rohit

2017-11-01

The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

Vision in a phase 3 trial of natalizumab for multiple sclerosis: relation to disability and quality of life.

PubMed

Chahin, Salim; Balcer, Laura J; Miller, Deborah M; Zhang, Annie; Galetta, Steven L

2015-03-01

Low-contrast visual acuity (LCVA), a sensitive measure of visual function in multiple sclerosis (MS), demonstrated treatment effects as a secondary outcome measure in the Phase 3 trial of natalizumab, AFFIRM. In these posttrial analyses, we studied the relation of visual function to quality of life (QOL), magnetic resonance imaging (MRI) measures, and Expanded Disability Status Scale (EDSS) scores. At baseline and at 52 and 104 weeks in AFFIRM, patients underwent binocular testing of LCVA (1.25% and 2.5% contrast) and high-contrast visual acuity (HCVA). Vision-specific QOL was assessed by the Impact of Visual Impairment Scale (IVIS), whereas the SF-36 Health Survey and Visual Analog Scale were administered as generic QOL measures and the EDSS as a measure of neurologic impairment. Among QOL measures, IVIS scores showed the most significant correlations with visual dysfunction at all time points in the trial (r= -0.25 to -0.45, P < 0.0001 for LCVA and HCVA). Higher MRI T1- and T2-lesion volumes were also associated with worse vision scores at all time points (P < 0.0001). Clinically meaningful worsening (progression) of LCVA was noted in substantial proportions of patients in AFFIRM and was prevalent even among those without EDSS progression over 2 years (21.9% with LCVA progression at 2.5% contrast; 26.2% at 1.25% contrast). HCVA worsened in only 3.7% of patients without EDSS progression. Loss of visual function, particularly as measured by LCVA, was common in AFFIRM, occurring in >20% of patients. Both LCVA and HCVA scores reflect vision-specific aspects of QOL, but LCVA provides information about disability progression not entirely captured by the EDSS. Vision represents a key dimension of outcome assessment for MS and adds valuable information on disability and QOL that can be useful to clinicians.

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.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

PubMed

Correale, Jorge; Gaitán, María I; Ysrraelit, María C; Fiol, Marcela P

2017-03-01

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Secondary and tertiary preventions of thyroid disease.

PubMed

Azizi, Fereidoun; Mehran, Ladan; Hosseinpanah, Farhad; Delshad, Hossein; Amouzegar, Atieh

2018-05-01

Secondary and tertiary preventions are concerned with the recognition of the disease process in a very early stage and delay in progression to complete disease and minimization of complications and the impact of illness. All articles related to secondary and tertiary prevention of thyroid diseases were reviewed. Using related key words, articles published between 2001 and 2015 were evaluated, categorized, and analyzed. In secondary prevention, congenital hypothyroidism and subclinical hypo and hyperthyroidism are equally important. Routine screening of patients with multinodular goiter by either ultrasonography or calcitonin is a controversial issue, while calcitonin assessments in medullary cancer and RET in family members are recommended. Screening of thyroid disease in pregnancy is limited to those with risk factors. Views regarding the importance of thyroid autoimmunity in secondary prevention are also presented. In tertiary prevention, prescribing excessive doses of levothyroxine, in the elderly in particular and appropriate care of all patients to avoid progression and complications are the key issues. Optimization of management of thyroid diseases requires timely screening, prevention of progression to more sever disease, optimal medical care, and avoidance of iatrogenic conditions.

Pembrolizumab versus the standard of care for relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment comparison.

PubMed

Keeping, Sam; Wu, Elise; Chan, Keith; Mojebi, Ali; Ferrante, Shannon Allen; Balakumaran, Arun

2018-05-15

There is significant unmet need among patients with relapsed and refractory classical Hodgkin's lymphoma (RRcHL) who have failed multiple lines of therapy, including brentuximab vedotin (BV). Pembrolizumab, an immune checkpoint inhibitor, is one possible treatment solution for this population. The objective of this study was to compare progression-free survival (PFS) with standard of care (SOC) versus pembrolizumab in previously BV treated RRcHL patients. A systematic literature review identified one observational study (Cheah et al., 2016) of SOC that was suitable for comparison with KEYNOTE-087, the principal trial of pembrolizumab in this population. Both naïve and population-adjusted (using outcomes regression) pairwise indirect comparisons were conducted. The primary analysis included all patients who had failed BV, with a secondary analysis conducted including only those known to have failed BV that was part of definitive treatment. In the primary analysis, SOC was inferior to pembrolizumab in both the unadjusted comparison (HR 5.00 [95% confidence interval (CI) 3.56-7.01]) and the adjusted comparison (HR 6.35 [95% CI 4.04-9.98]). These HRs increased to 5.16 (95% CI 3.61-7.38) and 6.56 (95% CI 4.01-10.72), respectively, in the secondary analysis. Pembrolizumab offers a significant improvement in PFS compared to SOC in this population.

Diagnosing Secondary Students' Misconceptions of Photosynthesis and Respiration in Plants Using a Two-Tier Multiple Choice Instrument.

ERIC Educational Resources Information Center

Haslam, Filocha; Treagust, David F.

1987-01-01

Describes a multiple-choice instrument that reliably and validly diagnoses secondary students' understanding of photosynthesis and respiration in plants. Highlights the consistency of students' misconceptions across secondary levels and indicates a high percentage of students have misconceptions regarding plant physiology. (CW)

Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment.

PubMed

Gulley, James L; Madan, Ravi A; Pachynski, Russell; Mulders, Peter; Sheikh, Nadeem A; Trager, James; Drake, Charles G

2017-04-01

Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ability Grouping in English Secondary School: Effects on Attainment in English, Mathematics, and Science.

ERIC Educational Resources Information Center

Ireson, Judith; Hallam, Susan; Hack, Sarah; Clark, Helen; Plewis, Ian

2002-01-01

Studied the impact of ability grouping on attainment in a cohort of year-9 students in 45 mixed secondary schools in England representing a variety of grouping practices. In mathematics, students at higher levels by year 6 make more progress in sets, but those in lower levels make more progress in mixed ability classes. Discusses educational…

The Soil Biota Composition along a Progressive Succession of Secondary Vegetation in a Karst Area

PubMed Central

He, Xunyang; Liu, Lu; Wang, Kelin

2014-01-01

Karst ecosystems are fragile and are in many regions degraded by anthropogenic activities. Current management of degraded karst areas focuses on aboveground vegetation succession or recovery and aims at establishing a forest ecosystem. Whether progressive succession of vegetation in karst areas is accompanied by establishment of soil biota is poorly understood. In the present study, soil microbial and nematode communities, as well as soil physico-chemical properties were studied along a progressive succession of secondary vegetation (from grassland to shrubland to forest) in a karst area in southwest China. Microbial biomass, nematode density, ratio of fungal to bacterial biomass, nematode structure index, and nematode enrichment index decreased with the secondary succession in the plant community. Overall, the results indicated a pattern of declines in soil biota abundance and food web complexity that was associated with a decrease in soil pH and a decrease in soil organic carbon content with the progressive secondary succession of the plant community. Our findings suggest that soil biota amendment is necessary during karst ecosystem restoration and establishment and management of grasslands may be feasible in karst areas. PMID:25379741

The role of free radicals in traumatic brain injury.

PubMed

O'Connell, Karen M; Littleton-Kearney, Marguerite T

2013-07-01

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

Hypothalamic hamartoma: is the epileptogenic zone always hypothalamic? Arguments for independent (third stage) secondary epileptogenesis.

PubMed

Scholly, Julia; Valenti, Maria-Paola; Staack, Anke M; Strobl, Karl; Bast, Thomas; Kehrli, Pierre; Steinhoff, Bernhard J; Hirsch, Edouard

2013-12-01

Gelastic seizures associated with hypothalamic hamartomas (HHs) are a clinicoradiologic syndrome presenting with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, electroencephalography (EEG) abnormalities, precocious puberty, behavioral disturbances, and progressive cognitive deterioration. Surgery in adults provides seizure freedom in only one third of patients. The poor results of epilepsy surgery could be explained by an extrahypothalamic epileptogenic zone. The existence of an independent, secondary epileptogenic area with persistent seizures after resection of the presumably primary lesion supports the concept of a "hypothalamic plus" epilepsy. "Hypothalamic plus" epilepsy could be related to either an extrahypothalamic structural lesion (visible on magnetic resonance imaging [MRI] or on neuropathology) or if the former is absent, to a functional alteration with enhanced epileptogenic properties due to a process termed secondary epileptogenesis. We report two patients with gelastic seizures with HH (gelastic seizures isolated or associated with dyscognitive seizures of temporal origin). Both patients underwent two-step surgery: first an endoscopic resection of the HH, followed at a later time by temporal lobectomy. Both patients became seizure-free only after the temporal lobectomy. In both cases, neuropathology failed to demonstrate a significant structural lesion in the temporal lobe. To our knowledge, for the first time, these two cases suggest the existence of independent secondary epileptogenesis in humans. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

[Chemical peritonitis after a bladder lesion during a cesarean section. A case report and literature review].

PubMed

Castro-Cuenca, Alejandro; Ángel-Muller, Edith; González-Carrillo, Viviana Andrea

2015-02-01

This paper reviews the case of a patient who underwent a cesarean surgery and re-entered with an oral way intolerance, postprandial emesis, abdominal pain and clear-fluid exit from surgical wound. After possible bladder injury and secondary chemistry peritonitis, the patient was taken to surgery where the diagnosis was confirmed, and the correction of bladder injury as well as peritoneal lavage were performed, it antibiotic therapy for three days and the patient had satisfactory evolution. Bladder injury is a rare complication of cesarean section with an estimated incidence between 0.0016 and 0.94%; but if it is not diagnosed intraoperative it can trigger a clinical setting of secondary chemical peritonitis, due to secondary irritation of the peritoneum. Chemical peritonitis is among the classification of secondary peritonitis. Within the pathophysiology, the mechanical, chemical or bacterial stimulus generates an inflammatory reaction, with progressive generation of exudate, leukocytes and fibrin deposit, which injure mesothelial cells, disrupt the defense and maintenance of peritoneal homeostasis, triggering serious complications, which can lead to multiple organ failure and death. The chemical peritonitis should be suspected with the clinical setting and the risk factors of recent surgical history and timely management should be instituted properly with correction of the cause, antimicrobial treatment, blood volume therapy and nutritional support, which leads to a favorable outcome for the patient and improves survival with fewer complications.

The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO

PubMed Central

Fratter, C.; Gorman, G.S.; Stewart, J.D.; Buddles, M.; Smith, C.; Evans, J.; Seller, A.; Poulton, J.; Roberts, M.; Hanna, M.G.; Rahman, S.; Omer, S.E.; Klopstock, T.; Schoser, B.; Kornblum, C.; Czermin, B.; Lecky, B.; Blakely, E.L.; Craig, K.; Chinnery, P.F.; Turnbull, D.M.; Horvath, R.; Taylor, R.W.

2010-01-01

Background: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease. Methods: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations. Results: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants. Conclusions: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy. GLOSSARY adPEO = autosomal dominant progressive external ophthalmoplegia; COX = cytochrome c oxidase; IOSCA = infantile-onset spinocerebellar ataxia; mtDNA = mitochondrial DNA; PEO = progressive external ophthalmoplegia; SANDO = sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; SDH = succinate dehydrogenase. PMID:20479361

Secondary eyewall formation as a progressive boundary layer response

NASA Astrophysics Data System (ADS)

Abarca, S. F.; Montgomery, M. T.; Bell, M. M.

2012-12-01

The robust observational (satellite based) evidence that secondary eyewalls are common features in major hurricanes contrasts with the scarce in situ observations of the phenomena and its life cycle. This lack of observations has resulted in an incomplete understanding of the dynamics of secondary eyewall formation (SEF). A wide variety of physical processes have been invoked to explain SEF, but only the recently proposed theory of a progressive boundary layer control in SEF has been supported by a variety of full physics mesoscale numerical integrations. The RAINEX field project provided unique observations of the secondary eyewall of Hurricane Rita (2005) both before and during the time Rita exhibited a clear secondary eyewall structure. These observations have contributed to the advancement of the understanding of the secondary eyewall phenomenon. However, in the RAINEX experiment, there was limited data sampling during the development of the secondary wind maxima, thereby precluding a complete observational investigation of the dynamics of SEF. In this presentation we adopt an azimuthally-averaged perspective of the flow dynamics and we test the newly proposed theory of a progressive boundary layer control on SEF. Specifically, we use both RAINEX data as well as data from high resolution, full physics mesoscale numerical simulations to initialize and force an axisymmetric slab boundary layer model with radial diffusion included. The objective is to investigate whether such a reduced boundary layer model can generate secondary wind maxima as a response to environments like those that result in SEF in nature and in full physics simulations.

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.

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.

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.

HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone

PubMed Central

Day, Kathleen C.; Hiles, Guadalupe Lorenzatti; Kozminsky, Molly; Dawsey, Scott J.; Paul, Alyssa; Broses, Luke J.; Shah, Rajal; Kunja, Lakshmi P.; Hall, Christopher; Palanisamy, Nallasivam; Daignault-Newton, Stephanie; El-Sawy, Layla; Wilson, Steven James; Chou, Andrew; Ignatoski, Kathleen Woods; Keller, Evan; Thomas, Dafydd; Nagrath, Sunitha; Morgan, Todd; Day, Mark L.

2016-01-01

Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites. PMID:27793843

Testing Mediation Using Multiple Regression and Structural Equation Modeling Analyses in Secondary Data

ERIC Educational Resources Information Center

Li, Spencer D.

2011-01-01

Mediation analysis in child and adolescent development research is possible using large secondary data sets. This article provides an overview of two statistical methods commonly used to test mediated effects in secondary analysis: multiple regression and structural equation modeling (SEM). Two empirical studies are presented to illustrate the…

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.

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.

On the interrelation of multiplication and division in secondary school children.

PubMed

Huber, Stefan; Fischer, Ursula; Moeller, Korbinian; Nuerk, Hans-Christoph

2013-01-01

Each division problem can be transformed into as a multiplication problem and vice versa. Recent research has indicated strong developmental parallels between multiplication and division in primary school children. In this study, we were interested in (i) whether these developmental parallels persist into secondary school, (ii) whether similar developmental parallels can be observed for simple and complex problems, (iii) whether skill level modulates this relationship, and (iv) whether the correlations are specific and not driven by general cognitive or arithmetic abilities. Therefore, we assessed performance of 5th and 6th graders attending two secondary school types of the German educational system in simple and complex multiplication as well as division while controlling for non-verbal intelligence, short-term memory, and other arithmetic abilities. Accordingly, we collected data from students differing in skills levels due to either age (5th < 6th grade) or school type (general < intermediate secondary school). We observed moderate to strong bivariate and partial correlations between multiplication and division with correlations being higher for simple tasks but nevertheless reliable for complex tasks. Moreover, the association between simple multiplication and division depended on students' skill levels as reflected by school types, but not by age. Partial correlations were higher for intermediate than for general secondary school children. In sum, these findings emphasize the importance of the inverse relationship between multiplication and division which persists into later developmental stages. However, evidence for skill-related differences in the relationship between multiplication and division was restricted to the differences for school types.

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.

Evaluating Secondary Students' Scientific Reasoning in Genetics Using a Two-Tier Diagnostic Instrument

NASA Astrophysics Data System (ADS)

Tsui, Chi-Yan; Treagust, David

2010-05-01

While genetics has remained as one key topic in school science, it continues to be conceptually and linguistically difficult for students with the concomitant debates as to what should be taught in the age of biotechnology. This article documents the development and implementation of a two-tier multiple-choice instrument for diagnosing grades 10 and 12 students' understanding of genetics in terms of reasoning. The pretest and posttest forms of the diagnostic instrument were used alongside other methods in evaluating students' understanding of genetics in a case-based qualitative study on teaching and learning with multiple representations in three Western Australian secondary schools. Previous studies have shown that a two-tier diagnostic instrument is useful in probing students' understanding or misunderstanding of scientific concepts and ideas. The diagnostic instrument in this study was designed and then progressively refined, improved, and implemented to evaluate student understanding of genetics in three case schools. The final version of the instrument had Cronbach's alpha reliability of 0.75 and 0.64, respectively, for its pretest and the posttest forms when it was administered to a group of grade 12 students (n = 17). This two-tier diagnostic instrument complemented other qualitative data collection methods in this research in generating a more holistic picture of student conceptual learning of genetics in terms of scientific reasoning. Implications of the findings of this study using the diagnostic instrument are discussed.

On the interrelation of multiplication and division in secondary school children

PubMed Central

Huber, Stefan; Fischer, Ursula; Moeller, Korbinian; Nuerk, Hans-Christoph

2013-01-01

Multiplication and division are conceptually inversely related: Each division problem can be transformed into as a multiplication problem and vice versa. Recent research has indicated strong developmental parallels between multiplication and division in primary school children. In this study, we were interested in (i) whether these developmental parallels persist into secondary school, (ii) whether similar developmental parallels can be observed for simple and complex problems, (iii) whether skill level modulates this relationship, and (iv) whether the correlations are specific and not driven by general cognitive or arithmetic abilities. Therefore, we assessed performance of 5th and 6th graders attending two secondary school types of the German educational system in simple and complex multiplication as well as division while controlling for non-verbal intelligence, short-term memory, and other arithmetic abilities. Accordingly, we collected data from students differing in skills levels due to either age (5th < 6th grade) or school type (general < intermediate secondary school). We observed moderate to strong bivariate and partial correlations between multiplication and division with correlations being higher for simple tasks but nevertheless reliable for complex tasks. Moreover, the association between simple multiplication and division depended on students' skill levels as reflected by school types, but not by age. Partial correlations were higher for intermediate than for general secondary school children. In sum, these findings emphasize the importance of the inverse relationship between multiplication and division which persists into later developmental stages. However, evidence for skill-related differences in the relationship between multiplication and division was restricted to the differences for school types. PMID:24133476

Creative Crisis: English Teacher Testimony of the Violent Writings of High School Youth

ERIC Educational Resources Information Center

Brown, Lori; Buskey, Frederick

2014-01-01

Violent writing is a real, yet rarely understood phenomenon in the secondary and post-secondary classroom. The 2007 Virginia Tech shooting tragedy sensationalized violent writing as a marker of disturbed and violent persons. However, violent writing comes in multiple forms and is composed for multiple reasons. As secondary schools wrestle with…

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

Treatment of Pediatric Septic Shock With the Surviving Sepsis Campaign Guidelines and PICU Patient Outcomes.

PubMed

Workman, Jennifer K; Ames, Stefanie G; Reeder, Ron W; Korgenski, E Kent; Masotti, Susan M; Bratton, Susan L; Larsen, Gitte Y

2016-10-01

The Surviving Sepsis Campaign recommends rapid recognition and treatment of severe sepsis and septic shock. Few reports have evaluated the impact of these recommendations in pediatrics. We sought to determine if outcomes in patients who received initial care compliant with the Surviving Sepsis Campaign time goals differed from those treated more slowly. Single center retrospective cohort study. Emergency department and PICU at an academic children's hospital. Three hundred twenty-one patients treated for septic shock in the emergency department and admitted directly to the PICU. None. The exposure was receipt of emergency department care compliant with the Surviving Sepsis Campaign recommendations (delivery of IV fluids, IV antibiotics, and vasoactive infusions within 1 hr of shock recognition). The primary outcome was development of new or progressive multiple organ dysfunction syndrome. Secondary outcomes included mortality, need for mechanical ventilation or vasoactive medications, and hospital and PICU length of stay. Of the 321 children studied, 117 received Surviving Sepsis Campaign compliant care in the emergency department and 204 did not. New or progressive multiple organ dysfunction syndrome developed in nine of the patients (7.7%) who received Surviving Sepsis Campaign compliant care and 25 (12.3%) who did not (p = 0.26). There were 17 deaths; overall mortality rate was 5%. There were no significant differences between groups in any of the secondary outcomes. Although only 36% of patients met the Surviving Sepsis Campaign guideline recommendation of bundled care within 1 hour of shock recognition, 75% of patients received the recommended interventions in less than 3 hours. Treatment for pediatric septic shock in compliance with the Surviving Sepsis Campaign recommendations was not associated with better outcomes compared with children whose initial therapies in the emergency department were administered more slowly. However, all patients were treated rapidly and we report low morbidity and mortality. This underscores the importance of rapid recognition and treatment of septic shock.

Applying Item Response Theory methods to design a learning progression-based science assessment

NASA Astrophysics Data System (ADS)

Chen, Jing

Learning progressions are used to describe how students' understanding of a topic progresses over time and to classify the progress of students into steps or levels. This study applies Item Response Theory (IRT) based methods to investigate how to design learning progression-based science assessments. The research questions of this study are: (1) how to use items in different formats to classify students into levels on the learning progression, (2) how to design a test to give good information about students' progress through the learning progression of a particular construct and (3) what characteristics of test items support their use for assessing students' levels. Data used for this study were collected from 1500 elementary and secondary school students during 2009--2010. The written assessment was developed in several formats such as the Constructed Response (CR) items, Ordered Multiple Choice (OMC) and Multiple True or False (MTF) items. The followings are the main findings from this study. The OMC, MTF and CR items might measure different components of the construct. A single construct explained most of the variance in students' performances. However, additional dimensions in terms of item format can explain certain amount of the variance in student performance. So additional dimensions need to be considered when we want to capture the differences in students' performances on different types of items targeting the understanding of the same underlying progression. Items in each item format need to be improved in certain ways to classify students more accurately into the learning progression levels. This study establishes some general steps that can be followed to design other learning progression-based tests as well. For example, first, the boundaries between levels on the IRT scale can be defined by using the means of the item thresholds across a set of good items. Second, items in multiple formats can be selected to achieve the information criterion at all the defined boundaries. This ensures the accuracy of the classification. Third, when item threshold parameters vary a bit, the scoring rubrics and the items need to be reviewed to make the threshold parameters similar across items. This is because one important design criterion of the learning progression-based items is that ideally, a student should be at the same level across items, which means that the item threshold parameters (d1, d 2 and d3) should be similar across items. To design a learning progression-based science assessment, we need to understand whether the assessment measures a single construct or several constructs and how items are associated with the constructs being measured. Results from dimension analyses indicate that items of different carbon transforming processes measure different aspects of the carbon cycle construct. However, items of different practices assess the same construct. In general, there are high correlations among different processes or practices. It is not clear whether the strong correlations are due to the inherent links among these process/practice dimensions or due to the fact that the student sample does not show much variation in these process/practice dimensions. Future data are needed to examine the dimensionalities in terms of process/practice in detail. Finally, based on item characteristics analysis, recommendations are made to write more discriminative CR items and better OMC, MTF options. Item writers can follow these recommendations to write better learning progression-based items.

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

PubMed

Lanzillo, Roberta; Quarantelli, Mario; Pozzilli, Carlo; Trojano, Maria; Amato, Maria Pia; Marrosu, Maria G; Francia, Ada; Florio, Ciro; Orefice, Giuseppe; Tedeschi, Gioacchino; Bellantonio, Paolo; Annunziata, Pasquale; Grimaldi, Luigi M; Comerci, Marco; Brunetti, Arturo; Bonavita, Vincenzo; Alfano, Bruno; Marini, Stefano; Brescia Morra, Vincenzo

2016-08-01

A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis. © The Author(s), 2015.

PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PubMed

Pfau, Maximilian; Lindner, Moritz; Goerdt, Lukas; Thiele, Sarah; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; Sadda, SriniVas R; Holz, Frank G; Fleckenstein, Monika

2018-05-16

To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

FIV diversity: FIVPle subtype composition may influence disease outcome in African lions

PubMed Central

Troyer, Jennifer L.; Roelke, Melody E.; Jespersen, Jillian M.; Baggett, Natalie; Buckley-Beason, Valerie; MacNulty, Dan; Craft, Meggan; Packer, Craig; Pecon-Slattery, Jill; O’Brien, Stephen J.

2011-01-01

Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIVFca) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIVPle) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIVPle subtypes, the data suggest that FIVPle subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations. PMID:21723622

Plaque surface irregularity and calcification length within carotid plaque predict secondary events in patients with coronary artery disease.

PubMed

Nonin, Shinichi; Iwata, Shinichi; Sugioka, Kenichi; Fujita, Suwako; Norioka, Naoki; Ito, Asahiro; Nakagawa, Masashi; Yoshiyama, Minoru

2017-01-01

Although comprehensive risk factor modification is recommended, a uniform management strategy does not necessarily prevent secondary events in patients with coronary artery disease (CAD). Therefore, identification of high-risk patients who may benefit from more intensive interventions may improve prognosis. Carotid ultrasound can reliably identify systemic atherosclerosis, and carotid plaque and intima-media thickness (IMT) are known independent risk factors for CAD. However, it is unclear whether findings on carotid ultrasound can improve prediction of secondary CAD events. The study population comprised 146 consecutive patients with CAD (mean age, 66 ± 9 years; 126 with angina pectoris, 20 with acute myocardial infarction). IMT, plaque score, plaque area, plaque surface irregularity, and calcification length (calculated by summing the calcified lesions within each plaque accompanied by acoustic shadow) were measured at baseline. Patients were followed for 10 years to ascertain secondary CAD events defined as hard major adverse cardiovascular events (MACE; cardiac death and acute myocardial infarction) and as total MACE (hard MACE and angina pectoris with coronary revascularization). Multiple regression analysis demonstrated that calcification length (p < 0.05) and plaque surface irregularity (p < 0.01) remained independently associated with total MACE after adjustment for age, sex, diabetes mellitus, dyslipidemia, hypertension, chronic kidney disease, smoking, and multivessel CAD. These findings suggest that the combination of calcification length and plaque surface irregularity has additional value beyond traditional risk classification. Intensive intervention for these high-risk patients may avoid or delay progression of atherosclerosis towards secondary CAD events. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Who Makes It to Secondary School? Determinants of Transition to Secondary Schools in Rural India

ERIC Educational Resources Information Center

Siddhu, Gaurav

2011-01-01

Despite considerable progress made, a significant proportion of children continue to drop out before reaching secondary school in India. This study investigates factors influencing parental decision-making with regard to children's secondary schooling in the context of a rural area of Uttar Pradesh. The study finds that cost, distance to the…

Double Morphology: Tertiary Syphilis and Acquired Immunodeficiency Syndrome-A Rare Association.

PubMed

Ngwanya, R M; Kakande, B; Khumalo, N P

2017-01-01

Human immunodeficiency virus (HIV) and Treponema pallidum coinfection is relatively common and accounts for about 25% of primary and secondary syphilis. Tertiary syphilis in HIV-uninfected and HIV-infected patients is vanishingly rare. This is most likely due to early treatment of cases of primary and secondary syphilis. There is rapid progression to tertiary syphilis in HIV-infected patients. A 49-year-old woman diagnosed with HIV Type 1 infection and cluster of differentiation 4 (CD4) count of 482 presented with a four-week history of multiple crusted plaques, nodules, and ulcers on her face, arms, and abdomen. Her past history revealed red painful eyes six months prior to this presentation. She had generalized lymphadenopathy, no alopecia, and no palmar-plantar or mucosal lesions. There were no features suggestive of secondary syphilis. Neurological examination was normal. Her rapid plasma reagin test was positive to a titer of 64. She was treated with Penicillin G 20 mu IVI daily for 2 weeks. Penicillin remains the treatment of choice in syphilitic infected HIV negative and HIV-infected individuals. In neurosyphilis, the dose of Penicillin GIVI is 18-24 mu daily for 10-14 days. This case report demonstrates the importance of excluding syphilis in any HIV-infected patient.

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.

Interobserver agreement on Poser's and the new McDonald's diagnostic criteria for multiple sclerosis.

PubMed

Zipoli, V; Portaccio, E; Siracusa, G; Pracucci, G; Sorbi, S; Amato, M P

2003-10-01

We assessed the interobserver agreement on the diagnosis of multiple sclerosis (MS) in a study sample consisting of 41 MS (15 relapsing remitting, two secondary progressive, five primary progressive and 19 presenting their first clinical attack) and three non-MS cases. Clinical and paraclinical information was recorded in standardized forms. Four neurologists were asked to make a diagnosis using Poser's and McDonald's criteria and to assess MRI scans according to the McDonald's guidelines. In terms of the kappa statistic (kappa), we found a moderate agreement on the overall diagnosis using both Poser's and McDonald's criteria (kappa, respectively 0.57 and 0.52). As for distinct diagnostic categories, we observed a moderate to substantial agreement for the three McDonald categories (range of kappa values 0.49-0.64) and a fair to substantial agreement for the nine Poser categories (range of kappa values 0.37-0.67). Taking into account clinical information, the agreement on dissemination over time was substantially higher (kappa = 0.69) than that found on dissemination over space (kappa = 0.46). In contrast, for MRI assessment, the agreement for spatial dissemination was substantial (kappa = 0.74) compared with the fair agreement (kappa = 0.25) yielded by dissemination over time. The new McDonald's criteria yield a good overall diagnostic reliability, and compare favourably with Poser's classification in terms of agreement on distinct diagnostic categories.

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: a voxel-based analysis study.

PubMed

Mallik, Shahrukh; Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia A M; Miller, David H; Chard, Declan T

2015-04-01

In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. © The Author(s), 2014.

Cognitive-Linguistic Deficit and Speech Intelligibility in Chronic Progressive Multiple Sclerosis

ERIC Educational Resources Information Center

Mackenzie, Catherine; Green, Jan

2009-01-01

Background: Multiple sclerosis is a disabling neurological disease with varied symptoms, including dysarthria and cognitive and linguistic impairments. Association between dysarthria and cognitive-linguistic deficit has not been explored in clinical multiple sclerosis studies. Aims: In patients with chronic progressive multiple sclerosis, the…

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.

PubMed

Lampson, Benjamin L; Brown, Jennifer R

2017-11-01

The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ. Expert Opinion: PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

[The diabetic child and the specifics of insulin therapy].

PubMed

Dirlewanger, M; Perrenoud, L; Castellsague-Perolini, M; Schwitzgebel, V M

2007-04-18

The incidence of diabetes type I has increased considerably in young children with an annual increase in Switzerland of 23,8% over the last ten years. The development of rapid acting and long acting analogues allowed a significant progress in treatment. Multiple daily insulin injections together with carbohydrate counting as well as continuous subcutaneous insulin infusion (CSII) improved the quality of life and led to an increased daily flexibility. The incidence of severe hypoglycaemic events has decreased at the same time metabolic control improved. The development of interstitial glucose measurement (online) coupled to the insulin pump represents a step further towards the artificial pancreas. The new therapeutic strategies of immunomodulation will hopefully lead to secondary and tertiary prevention of diabetes.

Research progress in radiation detectors, pattern recognition programs, and radiation damage determination in DNA

NASA Technical Reports Server (NTRS)

Baily, N. A.

1973-01-01

The radiological implications of statistical variations in energy deposition by ionizing radiation were investigated in the conduct of the following experiments: (1) study of the production of secondary particles generated by the passage of the primary radiation through bone and muscle; (2) the study of the ratio of nonreparable to reparable damage in DNA as a function of different energy deposition patterns generated by X rays versus heavy fast charged particles; (3) the use of electronic radiography systems for direct fluoroscopic tomography and for the synthesis of multiple planes and; (4) the determination of the characteristics of systems response to split fields having different contrast levels, and of minimum detectable contrast levels between the halves under realistic clinical situations.

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

Comprehensive Support for Peer Relationships at Secondary Transition

ERIC Educational Resources Information Center

Keay, Andy; Lang, Jane; Frederickson, Norah

2015-01-01

Peer relationships represent a major source of concern to children transitioning to secondary school. They also offer a potentially important source of support to adjustment and academic progress. However, strategies to support peer relationships at secondary transition have received little attention in previous research. This semi-structured…

Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.

PubMed

Du, G; Lewis, M M; Kanekar, S; Sterling, N W; He, L; Kong, L; Li, R; Huang, X

2017-05-01

Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms. © 2017 by American Journal of Neuroradiology.

Electromagnetic interference-aware transmission scheduling and power control for dynamic wireless access in hospital environments.

PubMed

Phunchongharn, Phond; Hossain, Ekram; Camorlinga, Sergio

2011-11-01

We study the multiple access problem for e-Health applications (referred to as secondary users) coexisting with medical devices (referred to as primary or protected users) in a hospital environment. In particular, we focus on transmission scheduling and power control of secondary users in multiple spatial reuse time-division multiple access (STDMA) networks. The objective is to maximize the spectrum utilization of secondary users and minimize their power consumption subject to the electromagnetic interference (EMI) constraints for active and passive medical devices and minimum throughput guarantee for secondary users. The multiple access problem is formulated as a dual objective optimization problem which is shown to be NP-complete. We propose a joint scheduling and power control algorithm based on a greedy approach to solve the problem with much lower computational complexity. To this end, an enhanced greedy algorithm is proposed to improve the performance of the greedy algorithm by finding the optimal sequence of secondary users for scheduling. Using extensive simulations, the tradeoff in performance in terms of spectrum utilization, energy consumption, and computational complexity is evaluated for both the algorithms.

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

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis.

PubMed

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

2017-08-01

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc . Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g. , oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g. , ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

Marching Backwards into the Future: The Introduction of the English Creative Music Movement in State Secondary Schools in Victoria, Australia

ERIC Educational Resources Information Center

Burke, Harry

2014-01-01

In 1910, Victoria established an elite form of state secondary education that remained essentially unchanged until the introduction of a progressive curriculum during the late 1960s. This radical and voluntary curriculum introduced child-centred learning and personal development skills to state secondary schools. Many state secondary music…

Multiple recurrent ischaemic strokes in a patient with cancer: is there a role for the initiation of anticoagulation therapy for secondary stroke prevention?

PubMed

Suero-Abreu, Giselle Alexandra; Cheng, Jia Zhen; Then, Ryna Karina

2017-06-03

A 52-year-old woman with a medical history of cervical and thyroid cancer, hypertension, dyslipidaemia, uncontrolled diabetes and heavy smoking was diagnosed with a new metastatic cholangiocarcinoma. While undergoing palliative chemotherapy, she developed dysarthria and left-sided weakness. Imaging studies showed multiple bilateral ischaemic strokes. On hospital days 2 and 5, she developed worsening neurological symptoms and imaging studies revealed new areas of ischaemia on respective days. Subsequent workup did not revealed a clear aetiology for the multiple ischaemic events and hypercoagulability studies were only significant for a mildly elevated serum D-dimer level. Although guidelines are unclear, full-dose anticoagulation with low molecular weight heparin was initiated given her high risk of stroke recurrence. She was discharged to acute rehabilitation but, within a month, she experienced complications of her malignant disease progression and a new pulmonary thromboembolism. The patient died soon after being discharged home with hospice care. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

PubMed Central

2014-01-01

This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke. PMID:25120903

Effects of NOx on the volatility of secondary organic aerosol from isoprene photooxidation

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

Xu, Lu; Kollman, Matthew S.; Song, Chen

2014-01-28

The effects of NOx on the volatility of the secondary organic aerosol (SOA) formed from isoprene photooxidation are investigated in environmental chamber experiments. Two types of experiments are performed. In HO2-dominant experiments, organic peroxy radicals (RO2) primarily react with HO2. In mixed experiments, RO2 reacts through multiple pathways. The volatility and oxidation state of isoprene SOA is sensitive to and displays a non-linear dependence on NOx levels. When initial NO/isoprene ratio is approximately 3 (ppbv:ppbv), SOA are shown to be most oxidized and least volatile, associated with the highest SOA yield. A High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS) is appliedmore » to characterize the key chemical properties of aerosols. While the composition of SOA in mixed experiments does not change substantially over time, SOA become less volatile and more oxidized as oxidation progresses in HO2-dominant experiments. Analysis of the SOA composition suggests that the further reactions of organic peroxides and alcohols may produce carboxylic acids, which might play a strong role in SOA aging.« less

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

PubMed

Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

2017-01-01

Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Reading in the Secondary School.

ERIC Educational Resources Information Center

Teaching English, 1976

1976-01-01

The topic of discussion of this issue of the journal "Teaching English" is reading instruction in the secondary school. Articles include "Reading in the Primary School" (Alastair Hendry), "Patterns of Progress" (Fergus McBride), "Teaching Reading--Whose Business?" (James Maxwell), "A Reading Policy for the Secondary School" (Iain McGillivray),…

Impaired heel to toe progression during gait is related to reduced ankle range of motion in people with Multiple Sclerosis.

PubMed

Psarakis, Michael; Greene, David; Moresi, Mark; Baker, Michael; Stubbs, Peter; Brodie, Matthew; Lord, Stephen; Hoang, Phu

2017-11-01

Gait impairment in people with Multiple Sclerosis results from neurological impairment, muscle weakness and reduced range of motion. Restrictions in passive ankle range of motion can result in abnormal heel-to-toe progression (weight transfer) and inefficient gait patterns in people with Multiple Sclerosis. The purpose of this study was to determine the associations between gait impairment, heel-to-toe progression and ankle range of motion in people with Multiple Sclerosis. Twelve participants with Multiple Sclerosis and twelve healthy age-matched participants were assessed. Spatiotemporal parameters of gait and individual footprint data were used to investigate group differences. A pressure sensitive walkway was used to divide each footprint into three phases (contact, mid-stance, propulsive) and calculate the heel-to-toe progression during the stance phase of gait. Compared to healthy controls, people with Multiple Sclerosis spent relatively less time in contact phase (7.8% vs 25.1%) and more time in the mid stance phase of gait (57.3% vs 33.7%). Inter-limb differences were observed in people with Multiple Sclerosis between the affected and non-affected sides for contact (7.8% vs 15.3%) and mid stance (57.3% and 47.1%) phases. Differences in heel-to-toe progression remained significant after adjusting for walking speed and were correlated with walking distance and ankle range of motion. Impaired heel-to-toe progression was related to poor ankle range of motion in people with Multiple Sclerosis. Heel-to-toe progression provided a sensitive measure for assessing gait impairments that were not detectable using standard spatiotemporal gait parameters. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treatment of progressive multiple sclerosis: what works, what does not, and what is needed.

PubMed

Feinstein, Anthony; Freeman, Jenny; Lo, Albert C

2015-02-01

Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Chronic cerebrospinal venous insufficiency (CCSVI) has recently been described as a vascular condition characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins. Despite a wide variability among studies, it has been found to be associated with MS. Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins. Study design and methods This is a multicenter, randomized, parallel group, blinded, sham-controlled trial to assess the efficacy and safety of PTA. Participants with relapsing remitting MS or secondary progressive MS and a sonographic diagnosis of CCSVI will be enrolled after providing their informed consent. Each participant will be centrally randomized to receive catheter venography and PTA or catheter venography and sham PTA. Two primary end points with respect to efficacy at 12 months are (1) a combined end point obtained through the integration of five functional indicators, walking, balance, manual dexterity, bladder control, and visual acuity, objectively measured by instruments; and (2) number of new brain lesions measured by T2-weighted MRI sequences. Secondary end points include annual relapse rate, change in Expanded Disability Status Scale score, proportion of patients with zero, one or two, or more than two relapses; fatigue; anxiety and depression; general cognitive state; memory/attention/calculus; impact of bladder incontinence; and adverse events. Six hundred seventy-nine patients will be recruited. The follow-up is scheduled at 12 months. Patients, treating neurologists, trained outcome assessors, and the statistician in charge of data analysis will be masked to the assigned treatment. Discussion The study will provide an answer regarding the efficacy of PTA on patients’ functional disability in balance, motor, sensory, visual and bladder function, cognitive status, and emotional status, which are meaningful clinical outcomes, beyond investigating the effects on inflammation. In fact, an important part of patients’ expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects. Trial registration Clinicaltrials.gov NCT01371760 PMID:23034121

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.

State-Level Cancer Quality Assessment and Research

PubMed Central

Lipscomb, Joseph; Gillespie, Theresa W.

2016-01-01

Over a decade ago, the Institute of Medicine called for a national cancer data system in the United States to support quality-of-care assessment and improvement, including research on effective interventions. Although considerable progress has been achieved in cancer quality measurement and effectiveness research, the nation still lacks a population-based data infrastructure for accurately identifying cancer patients and tracking services and outcomes over time. For compelling reasons, the most effective pathway forward may be the development of state-level cancer data systems, in which central registry data are linked to multiple public and private secondary sources. These would include administrative/claims files from Medicare, Medicaid, and private insurers. Moreover, such a state-level system would promote rapid learning by encouraging adoption of near-real-time reporting and feedback systems, such as the Commission on Cancer’s new Rapid Quality Reporting System. The groundwork for such a system is being laid in the state of Georgia, and similar work is advancing in other states. The pace of progress depends on the successful resolution of issues related to the application of information technology, financing, and governance. PMID:21799333

Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

NASA Astrophysics Data System (ADS)

Chang, Kelly C.; Trayanova, Natalia A.

2016-11-01

The occurrence of atrial fibrillation (AF) is associated with progressive changes in the calcium handling system of atrial myocytes. Calcium cycling instability has been implicated as an underlying mechanism of electrical alternans observed in patients who experience AF. However, the extent to which calcium-induced alternation of electrical activity in the atria contributes to arrhythmogenesis is unknown. In this study, we investigated the effects of calcium-driven alternans (CDA) on arrhythmia susceptibility in a biophysically detailed, 3D computer model of the human atria representing electrical and structural remodeling secondary to chronic AF. We found that elevated propensity to CDA rendered the atria vulnerable to ectopy-induced arrhythmia. It also increased the complexity and persistence of arrhythmias induced by fast pacing, with unstable scroll waves meandering and frequently breaking up to produce multiple wavelets. Our results suggest that calcium-induced electrical instability may increase arrhythmia vulnerability and promote increasing disorganization of arrhythmias in the chronic AF-remodeled atria, thus playing an important role in the progression of the disease.

The Uptake of Secondary Prevention by Adults with Intellectual and Developmental Disabilities

ERIC Educational Resources Information Center

Ouellette-Kuntz, H.; Cobigo, V.; Balogh, R.; Wilton, A.; Lunsky, Y.

2015-01-01

Background: Secondary prevention involves the early detection of disease while it is asymptomatic to prevent its progression. For adults with intellectual and developmental disabilities, secondary prevention is critical as they may not have the ability to recognize the early signs and symptoms of disease or lack accessible information about these.…

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.

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

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.

Genome-wide analysis of disease progression in age-related macular degeneration.

PubMed

Yan, Qi; Ding, Ying; Liu, Yi; Sun, Tao; Fritsche, Lars G; Clemons, Traci; Ratnapriya, Rinki; Klein, Michael L; Cook, Richard J; Liu, Yu; Fan, Ruzong; Wei, Lai; Abecasis, Gonçalo R; Swaroop, Anand; Chew, Emily Y; Weeks, Daniel E; Chen, Wei

2018-03-01

Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.

The Promise of Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease.

PubMed

Griffin, Tomás P; Martin, William Patrick; Islam, Nahidul; O'Brien, Timothy; Griffin, Matthew D

2016-05-01

Diabetes mellitus (DM) commonly leads to progressive chronic kidney disease despite current best medical practice. The pathogenesis of diabetic kidney disease (DKD) involves a complex network of primary and secondary mechanisms with both intra-renal and systemic components. Apart from inhibition of the renin angiotensin aldosterone system, targeting individual pathogenic mediators with drug therapy has not, thus far, been proven to have high clinical value. Stem or progenitor cell therapies offer an alternative strategy for modulating complex disease processes through suppressing multiple pathogenic pathways and promoting pro-regenerative mechanisms. Mesenchymal stem cells (MSCs) have shown particular promise based on their accessibility from adult tissues and their diverse mechanisms of action including secretion of paracrine anti-inflammatory and cyto-protective factors. In this review, the progress toward clinical translation of MSC therapy for DKD is critically evaluated. Results from animal models suggest distinct potential for systemic MSC infusion to favourably modulate DKD progression. However, only a few early phase clinical trials have been initiated and efficacy in humans remains to be proven. Key knowledge gaps and research opportunities exist in this field. These include the need to gain greater understanding of in vivo mechanism of action, to identify quantifiable biomarkers of response to therapy and to define the optimal source, dose and timing of MSC administration. Given the rising prevalence of DM and DKD worldwide, continued progress toward harnessing the inherent regenerative functions of MSCs and other progenitor cells for even a subset of those affected has potential for profound societal benefits.

Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib.

PubMed

Ignatius Ou, Sai-Hong; Azada, Michele; Hsiang, David J; Herman, June M; Kain, Tatiana S; Siwak-Tapp, Christina; Casey, Cameron; He, Jie; Ali, Siraj M; Klempner, Samuel J; Miller, Vincent A

2014-04-01

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.

Celiac disease causing severe osteomalacia: an association still present in Morocco!

PubMed

Tahiri, Latifa; Azzouzi, Hamida; Squalli, Ghita; Abourazzak, Fatimazahra; Harzy, Taoufik

2014-01-01

Celiac disease (CD), a malabsorption syndrome caused by hypersensitivity to gliadin fraction of gluten. CD can manifest with classic symptoms; however, significant myopathy and multiple fractures are rarely the predominant presentation of untreated celiac disease. Osteomalacia complicating celiac disease had become more and more rare. We describe here a case of osteomalacia secondary to a longstanding untreated celiac disease. This patient complained about progressive bone and muscular pain, weakness, fractures and skeletal deformities. Radiological and laboratory findings were all in favor of severe osteomalacia. Improvement of patient's weakness and laboratory abnormalities was obvious after treatment with gluten free diet, vitamin D, calcium and iron. This case affirms that chronic untreated celiac disease, can lead to an important bone loss and irreversible complications like skeletal deformities.

Celiac disease causing severe osteomalacia: an association still present in Morocco!

PubMed Central

Tahiri, Latifa; Azzouzi, Hamida; Squalli, Ghita; Abourazzak, Fatimazahra; Harzy, Taoufik

2014-01-01

Celiac disease (CD), a malabsorption syndrome caused by hypersensitivity to gliadin fraction of gluten. CD can manifest with classic symptoms; however, significant myopathy and multiple fractures are rarely the predominant presentation of untreated celiac disease. Osteomalacia complicating celiac disease had become more and more rare. We describe here a case of osteomalacia secondary to a longstanding untreated celiac disease. This patient complained about progressive bone and muscular pain, weakness, fractures and skeletal deformities. Radiological and laboratory findings were all in favor of severe osteomalacia. Improvement of patient's weakness and laboratory abnormalities was obvious after treatment with gluten free diet, vitamin D, calcium and iron. This case affirms that chronic untreated celiac disease, can lead to an important bone loss and irreversible complications like skeletal deformities. PMID:25667705

Visualization of metallodrugs in single cells by secondary ion mass spectrometry imaging.

PubMed

Wu, Kui; Jia, Feifei; Zheng, Wei; Luo, Qun; Zhao, Yao; Wang, Fuyi

2017-07-01

Secondary ion mass spectrometry, including nanoscale secondary ion mass spectrometry (NanoSIMS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), has emerged as a powerful tool for biological imaging, especially for single cell imaging. SIMS imaging can provide information on subcellular distribution of endogenous and exogenous chemicals, including metallodrugs, from membrane through to cytoplasm and nucleus without labeling, and with high spatial resolution and chemical specificity. In this mini-review, we summarize recent progress in the field of SIMS imaging, particularly in the characterization of the subcellular distribution of metallodrugs. We anticipate that the SIMS imaging method will be widely applied to visualize subcellular distributions of drugs and drug candidates in single cells, exerting significant influence on early drug evaluation and metabolism in medicinal and pharmaceutical chemistry. Recent progress of SIMS applications in characterizing the subcellular distributions of metallodrugs was summarized.

[Somatostatin analogs for the treatment of advanced, hormone-refractory prostate cancer: a possibility for secondary hormonal ablation?].

PubMed

Schilling, D; Küfer, R; Kruck, S; Stenzl, A; Kuczyk, M A; Merseburger, A S

2008-10-01

Almost all patients with hormone-refractory prostate cancer under primary androgen deprivation therapy will develop progression, frequently initially marked by an asymptomatic increase of prostate-specific antigen (PSA). Recent data showed that taxane-based chemotherapy offers significant survival benefit to patients with advanced prostate cancer; however, the toxic side effects frequently exert a significant negative impact on the quality of life. At the androgen-independent stage of the cancer, before becoming hormone refractory, progression might still be delayed by secondary manipulation of either androgen or confounding receptors and their signaling pathways. Secondary hormonal manipulations traditionally included antiandrogen withdrawal, second-line antiandrogens, direct adrenal androgen inhibitors, estrogens, and progestins.We discuss the mode of action and application of somatostatin analogs as an emerging secondary hormonal treatment concept in patients with advanced prostate cancer on the basis of the current literature.

Using Rasch Measurement to Validate an Instrument for Measuring the Quality of Classroom Teaching in Secondary Chemistry Lessons

ERIC Educational Resources Information Center

He, Peng; Liu, Xiufeng; Zheng, Changlong; Jia, Mengying

2016-01-01

This study intends to develop a standardized instrument for measuring classroom teaching and learning in secondary chemistry lessons. Based on previous studies and interviews with expert teachers, the progression of five quality levels was constructed hypothetically to represent the quality of chemistry lessons in Chinese secondary schools. The…

Access to Education in Bangladesh: Country Analytic Review of Primary and Secondary School

ERIC Educational Resources Information Center

Ahmed, Manzoor; Ahmed, Kazi Saleh; Khan, Nurul Islam; Ahmed, Romij

2007-01-01

This country analytical review examines the key issues in access to and participation in primary and secondary education in Bangladesh, with a special focus on areas and dimensions of exclusion. Against a background of overall progress, particularly in closing the gender gap in primary and secondary enrollment, the research applies a conceptual…

Democratization of Secondary Education in Malaysia: Attitudes towards Schooling and Educational Aspirations

ERIC Educational Resources Information Center

Tan, Yao Sua

2011-01-01

As a consequence of the democratization of secondary education in Malaysia beginning in the 1990s, many students who do not have academic credentials are allowed to progress to upper secondary education. This study examines the attitudes of these students towards two important aspects of schooling--namely, learning and examinations, as well as…

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: A voxel-based analysis study

PubMed Central

Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia AM; Miller, David H; Chard, Declan T

2015-01-01

Background: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). Methods: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. Results: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. Conclusions: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. PMID:25145689

Quantifying reactive transport processes governing arsenic mobility in a Bengal Delta aquifer

NASA Astrophysics Data System (ADS)

Rawson, Joey; Neidhardt, Harald; Siade, Adam; Berg, Michael; Prommer, Henning

2017-04-01

Over the last few decades significant progress has been made to characterize the extent and severity of groundwater arsenic pollution in S/SE Asia, and to understand the underlying geochemical processes. However, comparably little effort has been made to merge the findings from this research into quantitative frameworks that allow for a process-based quantitative analysis of observed arsenic behavior and predictions of its future fate. Therefore, this study developed and tested field-scale numerical modelling approaches to represent the primary and secondary geochemical processes associated with the reductive dissolution of Fe-oxy(hydr)oxides and the concomitant release of sorbed arsenic. We employed data from an in situ field experiment in the Bengal Delta Plain, which investigated the influence of labile organic matter (sucrose) on the mobility of Fe, Mn, and As. The data collected during the field experiment were used to guide our model development and to constrain the model parameterisation. Our results show that sucrose oxidation coupled to the reductive dissolution of Fe-oxy(hydr)oxides was accompanied by multiple secondary geochemical reactions that are not easily and uniquely identifiable and quantifiable. Those secondary reactions can explain the disparity between the observed Fe and As behavior. Our modelling results suggest that a significant fraction of the released As is scavenged through (co-)precipitation with newly formed Fe-minerals, specifically magnetite, rather than through sorption to pre-existing and freshly precipitated iron minerals.

Spatial Thinking as the Dimension of Progress in an Astronomy Learning Progression

ERIC Educational Resources Information Center

Plummer, Julia D.

2014-01-01

The big idea of "celestial motion", observational astronomy phenomena explained by the relative position and motion of objects in the solar system and beyond, is central to astronomy in primary and secondary education. In this paper, I argue that students' progress in developing productive, scientific explanations for this class of…

The Influence of Depression on the Progression of HIV: Direct and Indirect Effects

ERIC Educational Resources Information Center

Schuster, Randi; Bornovalova, Marina; Hunt, Elizabeth

2012-01-01

The authors suggest a theoretical model of pathways of HIV progression, with a focus on the contributions of depression--as well as secondary, behavioral and emotional variables. Literature was reviewed regarding (a) comorbid depression and the direct physiological effects on HIV progression and (b) intermediary factors between HIV and disease…

Students' Energy Concepts at the Transition Between Primary and Secondary School

NASA Astrophysics Data System (ADS)

Opitz, Sebastian T.; Harms, Ute; Neumann, Knut; Kowalzik, Kristin; Frank, Arne

2015-10-01

Energy is considered both a core idea and a crosscutting concept in science education. A thorough understanding of the energy concept is thought to help students learn about other (related) concepts within and across science subjects, thereby fostering scientific literacy. This study investigates students' progression in understanding the energy concept in biological contexts at the transition from primary to lower secondary school by employing a quantitative, cross-sectional study in grades 3-6 ( N = 540) using complex multiple-choice items. Based on a model developed in a previous study, energy concepts were assessed along four aspects of energy: (1) forms and sources of energy, (2) transfer and transformation, (3) degradation and dissipation, and (4) energy conservation. Two parallel test forms (A and B) indicated energy concept scores to increase significantly by a factor of 2.3 (A)/1.7 (B) from grade 3 to grade 6. Students were observed to progress in their understanding of all four aspects of the concept and scored highest on items for energy forms. The lowest scores and the smallest gain across grades were found for energy conservation. Based on our results, we argue that despite numerous learning opportunities, students lack a more integrated understanding of energy at this stage, underlining the requirement of a more explicit approach to teaching energy to young learners. Likewise, more interdisciplinary links for energy learning between relevant contexts in each science discipline may enable older students to more efficiently use energy as a tool and crosscutting concept with which to analyze complex content.

Baseline characteristics predict risk of progression and response to combined medical therapy for benign prostatic hyperplasia (BPH).

PubMed

Kozminski, Michael A; Wei, John T; Nelson, Jason; Kent, David M

2015-02-01

To better risk stratify patients, using baseline characteristics, to help optimise decision-making for men with moderate-to-severe lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) through a secondary analysis of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. After review of the literature, we identified potential baseline risk factors for BPH progression. Using bivariate tests in a secondary analysis of MTOPS data, we determined which variables retained prognostic significance. We then used these factors in Cox proportional hazard modelling to: i) more comprehensively risk stratify the study population based on pre-treatment parameters and ii) to determine which risk strata stood to benefit most from medical intervention. In all, 3047 men were followed in MTOPS for a mean of 4.5 years. We found varying risks of progression across quartiles. Baseline BPH Impact Index score, post-void residual urine volume, serum prostate-specific antigen (PSA) level, age, American Urological Association Symptom Index score, and maximum urinary flow rate were found to significantly correlate with overall BPH progression in multivariable analysis. Using baseline factors permits estimation of individual patient risk for clinical progression and the benefits of medical therapy. A novel clinical decision tool based on these analyses will allow clinicians to weigh patient-specific benefits against possible risks of adverse effects for a given patient. © 2014 The Authors. BJU International © 2014 BJU International.

Natural history of age-related lobular involution and impact on breast cancer risk.

PubMed

Radisky, Derek C; Visscher, Daniel W; Frank, Ryan D; Vierkant, Robert A; Winham, Stacey; Stallings-Mann, Melody; Hoskin, Tanya L; Nassar, Aziza; Vachon, Celine M; Denison, Lori A; Hartmann, Lynn C; Frost, Marlene H; Degnim, Amy C

2016-02-01

Age-related lobular involution (LI) is a physiological process in which the terminal duct lobular units of the breast regress as a woman ages. Analyses of breast biopsies from women with benign breast disease (BBD) have found that extent of LI is negatively associated with subsequent breast cancer development. Here we assess the natural course of LI within individual women, and the impact of progressive LI on breast cancer risk. The Mayo Clinic BBD cohort consists of 13,455 women with BBD from 1967 to 2001. The BBD cohort includes 1115 women who had multiple benign biopsies, 106 of whom had developed breast cancer. Within this multiple biopsy cohort, the progression of the LI process was examined by age at initial biopsy and time between biopsies. The relationship between LI progression and breast cancer risk was assessed using standardized incidence ratios and by Cox proportional hazards analysis. Women who had multiple biopsies were younger age and had a slightly higher family history of breast cancer as compared with the overall BBD cohort. Extent of LI at subsequent biopsy was greater with increasing time between biopsies and for women age 55 + at initial biopsy. Among women with multiple biopsies, there was a significant association of higher breast cancer risk among those with involution stasis (lack of progression, HR 1.63) as compared with those with involution progression, p = 0.036. The multiple biopsy BBD cohort allows for a longitudinal study of the natural progression of LI. The majority of women in the multiple biopsy cohort showed progression of LI status between benign biopsies, and extent of progression was highest for women who were in the perimenopausal age range at initial biopsy. Progression of LI status between initial and subsequent biopsy was associated with decreased breast cancer risk.

Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration.

PubMed

Viringipurampeer, Ishaq A; Gregory-Evans, Cheryl Y; Metcalfe, Andrew L; Bashar, Emran; Moritz, Orson L; Gregory-Evans, Kevin

2018-06-18

Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed by secondary cone cell death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due to incomplete knowledge of the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains a challenge. In particular, preventing secondary cone photoreceptor cell loss is a key goal in designing potential therapies. In this study, we identified the main drivers of rod cell death and secondary cone loss in the transgenic S334ter rhodopsin rat model, tested the efficacy of specific cell death inhibitors on retinal function, and compared the effect of combining drugs to target multiple pathways in the S334ter and P23H rhodopsin rat models. The primary driver of early rod cell death in the S334ter model was a caspase-dependent process, whereas cone cell death occurred though RIP3-dependent necroptosis. In comparison, rod cell death in the P23H model was via necroptotic signaling, whereas cone cell loss occurred through inflammasome activation. Combination therapy of four drugs worked better than the individual drugs in the P23H model but not in the S334ter model. These differences imply that treatment modalities need to be tailored for each genotype. Taken together, our data demonstrate that rationally designed genotype-specific drug combinations will be an important requisite to effectively target primary rod cell loss and more importantly secondary cone survival.

FIV diversity: FIV Ple subtype composition may influence disease outcome in African lions.

PubMed

Troyer, Jennifer L; Roelke, Melody E; Jespersen, Jillian M; Baggett, Natalie; Buckley-Beason, Valerie; MacNulty, Dan; Craft, Meggan; Packer, Craig; Pecon-Slattery, Jill; O'Brien, Stephen J

2011-10-15

Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIV(Fca)) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIV(Ple)) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIV(Ple) subtypes, the data suggest that FIV(Ple) subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations. Copyright © 2011 Elsevier B.V. All rights reserved.

Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.

PubMed

Ferreira de Freitas, Renato; Harding, Rachel J; Franzoni, Ivan; Ravichandran, Mani; Mann, Mandeep K; Ouyang, Hui; Lautens, Mark; Santhakumar, Vijayaratnam; Arrowsmith, Cheryl H; Schapira, Matthieu

2018-05-24

HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

Mycophenolate Mofetil for the Treatment of Multiple Sclerosis-associated Uveitis.

PubMed

Hedayatfar, Alireza; Falavarjani, Khalil Ghasemi; Soheilian, Masoud; Elmi Sadr, Navid; Modarres, Mehdi; Parvaresh, Mohammad Mehdi; Naseripour, Masood; Rohani, Mohammad; Almasi, Mostafa; Chee, Soon-Phaik

2017-06-01

To report the efficacy of mycophenolate mofetil (MMF) as adjunctive therapy for the treatment of multiple sclerosis (MS)-associated uveitis. In this retrospective, interventional case series, patients with MS-associated uveitis who were treated by MMF as an adjunct therapy to systemic corticosteroid were studied. Patients' demographics, clinical course, response to treatment, and complications were assessed. A total of 30 eyes of 15 patients with a mean age of 34.5 ± 8.3 years were studied. In three patients (20%), onset of uveitis preceded the diagnosis of MS. The course of MS was relapsing-remitting in 11 patients (73.3%) and secondary progressive in four patients (26.7%). At 1 year after institution of MMF, all the patients were on oral prednisolone ≤ 7.5 mg/day, all eyes were quiet without macular edema, and 53.3% of eyes gained visual improvement. Supplemental periocular and intraocular injections were needed during the first 6 months after starting MMF therapy. The systemic adverse effects were transient and minor in severity. MMF had beneficial effects on vision and intraocular inflammation with an acceptable safety profile.

Plasma cell leukaemia and other aggressive plasma cell malignancies

PubMed Central

Sher, Taimur; Miller, Kena C.; Deeb, George; Lee, Kelvin; Chanan-Khan, Asher

2014-01-01

Summary Extramedullary plasma cell cancers, such as plasma cell leukemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de-novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti-plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed. PMID:20701603

Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

DTIC Science & Technology

2016-02-01

14. ABSTRACT Athletes in contact sports who have sustained multiple concussive traumatic brain injuries are at high risk for delayed, progressive...pugilistica 3, 11 or ‘punch drunk’ syndrome 9, 12. US military personnel 13, 14 and others who have sustained multiple concussive traumatic brain...Progress to date: To date, none of the attempts to model progressive tau pathology after repetitive concussive TBI in mice has been optimal. Ongoing

Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

DTIC Science & Technology

2015-02-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT Athletes in contact sports who have sustained multiple concussive traumatic brain injuries are at high risk for...multiple concussive traumatic brain injuries 15-17 may also be at risk for this condition. Currently, there are no methods to identify progressive tau...after traumatic brain injury. Progress to date: To date, none of the attempts to model progressive tau pathology after repetitive concussive TBI in

Secondary sclerosing cholangitis in critically ill patients.

PubMed

Peña-Pérez, Carlos Alberto; Ponce-Medrano, Juan Alberto Díaz

2018-01-01

Primary sclerosing cholangitis (PSC) is a rare idiopathic condition with immunopathogenic mechanisms where there is chronic progressive destruction of the biliary tree. Secondary sclerosing cholangitis (SSC) is clinically comparable to PSC, but is caused by specific processes which directly damage the biliary tree; examples include recurrent pancreatitis, bile duct malignancy, congenital bile duct abnormalities. A new cause of SSC has been described during or following significant critical illness associated with severe respiratory insufficiency, vasopressor requirement, shock and sepsis. This condition rapidly progresses to cirrhosis, frequently requiring liver transplantation for definitive management. Copyright: © 2018 Permanyer.

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.

Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS)

PubMed Central

2012-01-01

Background Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). It involves damage to the myelin sheath surrounding axons and to the axons themselves. MS most often presents with a series of relapses and remissions but then evolves over a variable period of time into a slowly progressive form of neurological dysfunction termed secondary progressive MS (SPMS). The reasons for this change in clinical presentation are unclear. The absence of a diagnostic marker means that there is a lag time of several years before the diagnosis of SPMS can be established. At the same time, understanding the mechanisms that underlie SPMS is critical to the development of rational therapies for this untreatable stage of the disease. Results Using high performance liquid chromatography-coupled mass spectrometry (HPLC); we have established a highly specific and sensitive selected reaction monitoring (SRM) assay. Our multiplexed SRM assay has facilitated the simultaneous detection of surrogate peptides originating from 26 proteins present in cerebrospinal fluid (CSF). Protein levels in CSF were generally ~200-fold lower than that in human sera. A limit of detection (LOD) was determined to be as low as one femtomol. We processed and analysed CSF samples from a total of 22 patients with SPMS, 7 patients with SPMS treated with lamotrigine, 12 patients with non-inflammatory neurological disorders (NIND) and 10 healthy controls (HC) for the levels of these 26 selected potential protein biomarkers. Our SRM data found one protein showing significant difference between SPMS and HC, three proteins differing between SPMS and NIND, two proteins between NIND and HC, and 11 protein biomarkers showing significant difference between a lamotrigine-treated and untreated SPMS group. Principal component analysis (PCA) revealed that these 26 proteins were correlated, and could be represented by four principal components. Overall, we established an efficient platform to develop and verify protein biomarkers in CSF, which can be easily adapted to other proteins of interest related to neurodegenerative diseases. Conclusions A highly specific and sensitive multiplex SRM-MS assay was established for development and verification of CSF protein biomarkers in SPMS. Five proteins were found to be expressed significantly differently between the three cohorts, SPMS, NIND and HC and 11 proteins associated with lamotrigine treatment, which we expect will further our current understanding of SPMS disease pathology and/or therapeutic intervention. PMID:22846148

Reduced NAA-levels in the NAWM of patients with MS is a feature of progression. A study with quantitative magnetic resonance spectroscopy at 3 Tesla.

PubMed

Aboul-Enein, Fahmy; Krssák, Martin; Höftberger, Romana; Prayer, Daniela; Kristoferitsch, Wolfgang

2010-07-20

Reduced N-acetyl-aspartate (NAA) levels in magnetic resonance spectroscopy (MRS) may visualize axonal damage even in the normal appearing white matter (NAWM). Demyelination and axonal degeneration are a hallmark in multiple sclerosis (MS). To define the extent of axonal degeneration in the NAWM in the remote from focal lesions in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS). 37 patients with clinical definite MS (27 with RRMS, 10 with SPMS) and 8 controls were included. We used 2D (1)H-MR-chemical shift imaging (TR = 1500ms, TE = 135ms, nominal resolution 1ccm) operating at 3Tesla to assess the metabolic pattern in the fronto-parietal NAWM. Ratios of NAA to creatine (Cr) and choline (Cho) and absolute concentrations of the metabolites in the NAWM were measured in each voxel matching exclusively white matter on the anatomical T2 weighted MR images. No significant difference of absolute concentrations for NAA, Cr and Cho or metabolite ratios were found between RRMS and controls. In SPMS, the NAA/Cr ratio and absolute concentrations for NAA and Cr were significantly reduced compared to RRMS and to controls. In our study SPMS patients, but not RRMS patients were characterized by low NAA levels. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression.

Making Progress: The Use of Multiple Progress Reports to Enhance Advertising Students' Media Plan Term Projects

ERIC Educational Resources Information Center

Kritz, Gary H.; Lozada, Hector R.; Long, Mary M.

2007-01-01

Since the AACSB mandates that students demonstrate effective oral and written communication skills, it is imperative that business professors do what is necessary to improve such skills. The authors investigate whether the use of using multiple progress reports in an Advertising class project improves the final product. The data results show that…

What Works and What Fails? Evidence from Seven Popular Literacy "Catch-Up" Schemes for the Transition to Secondary School in England

ERIC Educational Resources Information Center

Gorard, Stephen; Siddiqui, Nadia; See, Beng Huat

2017-01-01

There are concerns that too many young people, from disadvantaged backgrounds, are moving into secondary education in the UK, and elsewhere, without the necessary literacy skills to make progress with the wider secondary school curriculum. A large number of interventions have been proposed to reduce this poverty gradient. This paper summarises the…

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design.

PubMed

Pujade-Lauraine, Eric; Fujiwara, Keiichi; Dychter, Samuel S; Devgan, Geeta; Monk, Bradley J

2018-03-27

Avelumab is a human anti-PD-L1 checkpoint inhibitor with clinical activity in multiple solid tumors. Here, we describe the rationale and design for JAVELIN Ovarian 200 (NCT02580058), the first randomized Phase III trial to evaluate the role of checkpoint inhibition in women with ovarian cancer. This three-arm trial is comparing avelumab administered alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory recurrent ovarian, fallopian tube or peritoneal cancer. Eligible patients are not preselected based on PD-L1 expression and may have received up to three prior lines of chemotherapy for platinum-sensitive disease, but none for resistant disease. Overall survival and progression-free survival are primary end points, and secondary end points include biomarker evaluations and pharmacokinetics.

The role of radiation therapy in the treatment of solitary plasmacytomas.

PubMed

Mayr, N A; Wen, B C; Hussey, D H; Burns, C P; Staples, J J; Doornbos, J F; Vigliotti, A P

1990-04-01

Between 1960 and 1985, 30 patients with solitary plasmacytomas were treated with radiotherapy at the University of Iowa: 13 patients with extramedullary plasmacytomas (EMP) and 17 with solitary plasmacytomas of bone (SPB). The local control rates were 92% for patients with EMP and 88% for those with SPB. Two of nine patients (22%) with EMP treated to the primary tumor only developed regional lymph node metastasis, indicating the need for elective irradiation of this area. The most common pattern of failure in both groups was progression to multiple myeloma. This occurred in 23% of the patients with EMP and 53% of those with SPB. The time course of progression to multiple myeloma differed for the two groups. All of those who progressed to multiple myeloma in the EMP group did so within 2 years, whereas a significant number of those in the SPB group progressed more than 5 years after initial therapy. None of five patients who received adjuvant chemotherapy in the SPB group progressed to multiple myeloma, compared to 75% (9/12) of the patients who did not receive chemotherapy.

Therapeutic possibilities and opportunities for comparative oncopathology.

PubMed

Kaiser, H E

1993-01-01

In reviewing abnormal growth, we may distinguish autonomous and nonautonomous growth processes. The highest diversification is reached in the autonomous non-self-limiting processes, the malignant neoplasms which, if not treated, are characterized by extensive growth and progression. In their development these processes exhibit autonomy on one hand and heterogeneity on the other. Neoplastic and related diseases are extremely complex. It is unacceptable to view them exclusively as genetic or metabolic diseases, or merely as the tumor itself, including its progressive stages, as evidenced in neoplastic metastasis. All these characteristics appear in the different types of neoplastic malignomas, e.g. genetic variations in the neoplastic cells from the normal cells of the parent tissue(s). Included here are tumor progression and cloning of the neoplastic cells, stagewise development of host metabolism and of tumor metabolism; neoplastic hereditary and endocrine-like syndromes as well as paraneoplastic syndromes and cachexia. Neoplastic progression, as observed in the metastatic cascade, derives from the cells of the primary tumor. In contrast, multiple primary tumors originate from different host tissues, whereas the syndromes themselves constitute a symptom complex developing in a neoplasm-bearing host and cannot be assigned to local or distant spread of neoplasms. The only possible explanation for these apparently contrasting processes lies in the interaction of tumor and host metabolism, which seemingly varies in tumor-bearing hosts and in those cases where the tumor has been surgical removed. Antigens and other compounds again show an increase with the usually ensuing secondary tumor spread, a course which provides the basis for most deaths from cancer.

Development and validation of a learning progression for change of seasons, solar and lunar eclipses, and moon phases

NASA Astrophysics Data System (ADS)

Testa, Italo; Galano, Silvia; Leccia, Silvio; Puddu, Emanuella

2015-12-01

In this paper, we report about the development and validation of a learning progression about the Celestial Motion big idea. Existing curricula, research studies on alternative conceptions about these phenomena, and students' answers to an open questionnaire were the starting point to develop initial learning progressions about change of seasons, solar and lunar eclipses, and Moon phases; then, a two-tier multiple choice questionnaire was designed to validate and improve them. The questionnaire was submitted to about 300 secondary students of different school levels (14 to 18 years old). Item response analysis and curve integral method were used to revise the hypothesized learning progressions. Findings support that spatial reasoning is a key cognitive factor for building an explanatory framework for the Celestial Motion big idea, but also suggest that causal reasoning based on physics mechanisms underlying the phenomena, as light flux laws or energy transfers, may significantly impact a students' understanding. As an implication of the study, we propose that the teaching of the three discussed astronomy phenomena should follow a single teaching-learning path along the following sequence: (i) emphasize from the beginning the geometrical aspects of the Sun-Moon-Earth system motion; (ii) clarify consequences of the motion of the Sun-Moon-Earth system, as the changing solar radiation flow on the surface of Earth during the revolution around the Sun; (iii) help students moving between different reference systems (Earth and space observer's perspective) to understand how Earth's rotation and revolution can change the appearance of the Sun and Moon. Instructional and methodological implications are also briefly discussed.

Will PEDF Therapy Reverse Chronic Demyelination and Prevent Axon Loss in a Murine Model of Progressive Multiple Sclerosis

DTIC Science & Technology

2015-12-01

Multiple Sclerosis ? PRINCIPAL INVESTIGATOR: David Pleasure MD CONTRACTING ORGANIZATION: University of California Davis, CA 95618 REPORT DATE...Murine Model of Progressive Multiple Sclerosis ? 5b. GRANT NUMBER W81XWH-12-1-0566 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Pleasure MD 5d...enhance central nervous system (CNS) remyelination and preserve CNS axons in mouse models of multiple sclerosis models. After determining the dosage of

Effect of secondary penicillin prophylaxis on valvular changes in patients with rheumatic heart disease in Far North Queensland.

PubMed

Haran, Shankar; Crane, Natalie; Kazi, Saniya; Axford-Haines, Louise; White, Andrew

2018-04-01

To determine the effect of secondary penicillin prophylaxis on echocardiographic diagnosed valvular changes in patients with rheumatic heart disease or history of acute rheumatic fever in the Townsville Health district. Patients with known were identified from the North Queensland register, serial echocardiogram results and number of secondary penicillin prophylaxis doses received in 2014 were collated. Descriptive statistics were utilised. Townsville Hospital and outreach clinics within the Townsville Health catchment zone. All patients diagnosed with acute rheumatic fever or rheumatic heart disease between 2010 and October 2013 who had serial echocardiograms prior to and post commencement of secondary penicillin prophylaxis were included. All patients were of Aboriginal or Torres Strait Islander descent. Progression of echocardiographic valvular changes and association with secondary penicillin prophylaxis compliance. Compliance with secondary penicillin prophylaxis among the study population was a secondary outcome measure. Twenty-three patients were recruited. Only those patients who were compliant with secondary penicillin prophylaxis had any improvement in valvular changes on echocardiogram. Four of six patients without any baseline valvular involvement developed new valvular changes. Seventy percent of patients received >75% of secondary penicillin prophylaxis doses. This small study of patients in Townsville suggests that with good secondary penicillin prophylaxis compliance there is regression of some cardiac lesions over time in people with rheumatic heart disease. Furthermore the natural history of acute rheumatic fever in the Indigenous population is progressive requiring strict adherence to secondary penicillin prophylaxis. Prospective studies or use of data from the nationwide RHD register and standardised reporting of cardiac echocardiograms will provide more robust evidence. © 2017 National Rural Health Alliance Inc.

Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

PubMed

Freeman, J A; Hendrie, W; Creanor, S; Jarrett, L; Barton, A; Green, C; Marsden, J; Rogers, E; Zajicek, J

2016-05-05

Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).

Text-Based Argumentation with Multiple Sources: A Descriptive Study of Opportunity to Learn in Secondary English Language Arts, History, and Science

ERIC Educational Resources Information Center

Litman, Cindy; Marple, Stacy; Greenleaf, Cynthia; Charney-Sirott, Irisa; Bolz, Michael J.; Richardson, Lisa K.; Hall, Allison H.; George, MariAnne; Goldman, Susan R.

2017-01-01

This study presents a descriptive analysis of 71 videotaped lessons taught by 34 highly regarded secondary English language arts, history, and science teachers, collected to inform an intervention focused on evidence-based argumentation from multiple text sources. Studying the practices of highly regarded teachers is valuable for identifying…

Making Meaning with Multimedia in Secondary English Language Arts: A Multiple Case Study

ERIC Educational Resources Information Center

Mahoney, Kerrigan Rose

2016-01-01

The purpose of this multiple case study was to learn about how secondary English language arts (ELA) teachers help students to make meaning with multimedia. The study focused on how and why teachers plan and implement meaning-making learning experiences. The cases represent the experiences and perspectives of five ELA teachers who use digital and…

Fatal case of Herbaspirillum seropedicae bacteremia secondary to pneumonia in an end-stage renal disease patient with multiple myeloma.

PubMed

Suwantarat, Nuntra; Adams, La'Tonzia L; Romagnoli, Mark; Carroll, Karen C

2015-08-01

Herbaspirillum spp. are rare causes of human infections associated primarily with bacteremia in cancer patients. We report the first fatal case of bacteremia secondary to pneumonia caused by Herbaspirillum seropedicae in a 65-year-old man with end-stage renal disease and multiple myeloma. Copyright © 2015 Elsevier Inc. All rights reserved.

Effectiveness of applying progressive muscle relaxation technique on quality of life of patients with multiple sclerosis.

PubMed

Ghafari, Somayeh; Ahmadi, Fazlolah; Nabavi, Masoud; Anoshirvan, Kazemnejad; Memarian, Robabe; Rafatbakhsh, Mohamad

2009-08-01

To identify the effects of applying Progressive Muscle Relaxation Technique on Quality of Life of patients with multiple Sclerosis. In view of the growing caring options in Multiple Sclerosis, improvement of quality of life has become increasingly relevant as a caring intervention. Complementary therapies are widely used by multiple sclerosis patients and Progressive Muscle Relaxation Technique is a form of complementary therapies. Quasi-experimental study. Multiple Sclerosis patients (n = 66) were selected with no probability sampling then assigned to experimental and control groups (33 patients in each group). Means of data collection included: Individual Information Questionnaire, SF-8 Health Survey, Self-reported checklist. PMRT performed for 63 sessions by experimental group during two months but no intervention was done for control group. Statistical analysis was done by SPSS software. Student t-test showed that there was no significant difference between two groups in mean scores of health-related quality of life before the study but this test showed a significant difference between two groups, one and two months after intervention (p < 0.05). anova test with repeated measurements showed that there is a significant difference in mean score of whole and dimensions of health-related quality of life between two groups in three times (p < 0.05). Although this study provides modest support for the effectiveness of Progressive Muscle Relaxation Technique on quality of life of multiple sclerosis patients, further research is required to determine better methods to promote quality of life of patients suffer multiple sclerosis and other chronic disease. Progressive Muscle Relaxation Technique is practically feasible and is associated with increase of life quality of multiple sclerosis patients; so that health professionals need to update their knowledge about complementary therapies.

A qualitative investigation of lay perspectives of diagnosis and self-management strategies employed by people with progressive multiple sclerosis.

PubMed

Frost, Julia; Grose, Jane; Britten, Nicky

2017-05-01

This article explores how people with progressive multiple sclerosis give meaning to their experiences. It builds upon the self-management literature, which has captured the tension between the desire for retaining normalcy and the increasing burden of self-management associated with chronic disease progression. This repeat interview study is empirically grounded in 28 interviews with 14 people with progressive multiple sclerosis. We identified gender differences in diagnosis-seeking which impacted subsequent sense-making. Male respondents found a diagnosis of multiple sclerosis difficult to come to terms with, and an enduring sense of loss or anger could inhibit further sense-making. A diagnosis of multiple sclerosis was more difficult to obtain for women respondents, and any sense of certainty that diagnosis provided framed their subsequent sense-making strategies. The complex sequelae of multiple sclerosis require that self-management strategies are both contextual and timely, although even the most accomplished self-managers can lose their sense of self with neurodegeneration. Disease progression can be associated with suicidal ideation, suggesting the need for greater dialogue to ensure that people with multiple sclerosis are adequately supported to fulfil their quality of life at all stages of neurodegeneration. These lay perspectives emphasise the articulation of affect rather than the rendering of a medical diagnosis, although diagnosis may provide a degree of certainty in the short term. The ethos of self-management ensures people attempt to retain their sense of 'normality' and existent social roles for as long as possible, but this ethos can negate both one's ability to self-manage and the management of self.

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.

Repeat Intracranial Expansion After Skull Regrowth in Hyperostotic Disease: Technical Note.

PubMed

Wong, Timothy; Herschman, Yehuda; Patel, Nitesh V; Patel, Tushar; Hanft, Simon

2017-06-01

Camurati-Engelmann disease (CED) is a rare, autosomal-dominant genetic disorder resulting in hyperostosis of the long bones and skull. Patients often develop cranial nerve dysfunction and increased intracranial pressure secondary to stenosis of nerve foramina and hyperostosis. Surgical decompression may provide symptomatic relief in select patients; however, a small number of reports document the recurrence of symptoms due to bony regrowth. We present a patient who had been treated previously with bilateral frontal and parietal craniotomy who experienced recurrence of symptoms due to reossification of her cranial bones. This report underscores the progressive nature of CED and its influence on surgical management. Furthermore, we propose a novel surgical approach with multiple craniectomies and titanium mesh cranioplasties that could potentially offer long-term symptomatic relief. A 46-year-old female patient with CED who was treated with ventriculoperitoneal shunting, posterior fossa decompression, and multiple craniotomies 2 decades prior presented with signs and symptoms of increased intracranial pressure. Studies of the skull at presentation demonstrated rethickening of cranial bones that resulted in severely decreased intracranial volume. A radical craniectomy, requiring 4 separate bone flaps made up of bilateral frontal and parietal bones, was performed. The remaining coronal and sagittal bony struts were drilled to approximately 1 cm thick. Cranioplasties with 4 separate titanium meshes were performed to preserve the natural contour of the patient's skull. Although surgical decompression could provide some patients with CED symptomatic relief, clinicians should consider managing CED as a chronic condition. To the authors' knowledge, this is one of few case reports documenting the recurrence of symptoms in a patient with CED treated by surgical intervention. Furthermore, we propose that multiple craniectomies with titanium mesh cranioplasties confer more permanent symptomatic control, and, more importantly, lower the risk of recurrence secondary to cranial hyperostosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Restless leg syndrome, sleep quality and fatigue in multiple sclerosis patients.

PubMed

Moreira, N C V; Damasceno, R S; Medeiros, C A M; Bruin, P F C de; Teixeira, C A C; Horta, W G; Bruin, V M S de

2008-10-01

We have tested the hypothesis that restless leg syndrome (RLS) is related to quality of sleep, fatigue and clinical disability in multiple sclerosis (MS). The diagnosis of RLS used the four minimum criteria defined by the International Restless Legs Syndrome Study Group. Fatigue was assessed by the Fatigue Severity Scale (FSS >27), quality of sleep by the Pittsburgh Sleep Quality Index (PSQI >6), excessive daytime sleepiness by the Epworth Sleepiness Scale (ESS >10) and clinical disability by the Expanded Disability Status Scale (EDSS). Forty-four patients (32 women) aged 14 to 64 years (43 +/- 14) with disease from 0.4 to 23 years (6.7 +/- 5.9) were evaluated. Thirty-five were classified as relapsing-remitting, 5 as primary progressive and 4 as secondary progressive. EDSS varied from 0 to 8.0 (3.6 +/- 2.0). RLS was detected in 12 cases (27%). Patients with RLS presented greater disability (P = 0.01), poorer sleep (P = 0.02) and greater levels of fatigue (P = 0.03). Impaired sleep was present in 23 (52%) and excessive daytime sleepiness in 3 cases (6.8%). Fatigue was present in 32 subjects (73%) and was associated with clinical disability (P = 0.000) and sleep quality (P = 0.002). Age, gender, disease duration, MS pattern, excessive daytime sleepiness and the presence of upper motor neuron signs were not associated with the presence of RLS. Fatigue was best explained by clinical disability and poor sleep quality. Awareness of RLS among health care professionals may contribute to improvement in MS management.

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.

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

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis

PubMed Central

Haselkorn, Jodie K.; Hughes, Christina; Rae-Grant, Alex; Henson, Lily Jung; Bever, Christopher T.; Lo, Albert C.; Brown, Theodore R.; Kraft, George H.; Getchius, Thomas; Gronseth, Gary; Armstrong, Melissa J.; Narayanaswami, Pushpa

2015-01-01

Objective: To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). Methods: We systematically searched the literature (1970–2013) and classified articles using 2004 American Academy of Neurology criteria. Results: This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0–6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0–8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2–6.5) (1 Class II). PMID:26598432

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.

Surgical Management of Encapsulating Peritoneal Sclerosis: A Case Report in Kidney Transplant Patient

PubMed Central

Talanian, M.; Azari, F.; Agarwal, A.

2018-01-01

Introduction Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome of progressive fibrotic change in response to prolonged, repetitive, and typically severe insult to the peritoneal mesothelium, often occurring in the setting of peritoneal dialysis (PD). Clear guidelines for successful management remain elusive. We describe the successful surgical management of EPS in a 28-year-old male s/p deceased donor kidney transplant for end-stage renal disease (ESRD) secondary to focal segmental glomerulosclerosis (FSGS). This patient received PD for 7 years but changed to hemodialysis (HD) in the year of transplant due to consistent signs and symptoms of underdialysis. EPS was visualized at the time of transplant. Despite successful renal transplantation, EPS progressed to cause small bowel obstruction (SBO) requiring PEG-J placement for enteral nutrition and gastric decompression. The patient subsequently developed a chronic gastrocutaneous fistula necessitating chronic TPN and multiple admissions for pain crises and bowel obstruction. He was elected to undergo surgical intervention due to deteriorating quality of life and failure to thrive. Surgical management included an exploratory laparotomy with extensive lysis of adhesions (LOA), repair of gastrocutaneous fistula, and end ileostomy with Hartmann's pouch. Postoperative imaging confirmed resolution of the SBO, and the patient was transitioned to NGT feeds and eventually only PO intake. He is continuing with PO nutrition, gaining weight, and free from dialysis. Conclusion Surgical intervention with LOA and release of small intestine can be successful for definitive management of EPS in the proper setting. In cases such as this, where management with enteral nutrition fails secondary to ongoing obstructive episodes, surgical intervention can be pursued in the interest of preserving quality of life. PMID:29682387

Surgical Management of Encapsulating Peritoneal Sclerosis: A Case Report in Kidney Transplant Patient.

PubMed

Shahbazov, R; Talanian, M; Alejo, J L; Azari, F; Agarwal, A; Brayman, K L

2018-01-01

Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome of progressive fibrotic change in response to prolonged, repetitive, and typically severe insult to the peritoneal mesothelium, often occurring in the setting of peritoneal dialysis (PD). Clear guidelines for successful management remain elusive. We describe the successful surgical management of EPS in a 28-year-old male s/p deceased donor kidney transplant for end-stage renal disease (ESRD) secondary to focal segmental glomerulosclerosis (FSGS). This patient received PD for 7 years but changed to hemodialysis (HD) in the year of transplant due to consistent signs and symptoms of underdialysis. EPS was visualized at the time of transplant. Despite successful renal transplantation, EPS progressed to cause small bowel obstruction (SBO) requiring PEG-J placement for enteral nutrition and gastric decompression. The patient subsequently developed a chronic gastrocutaneous fistula necessitating chronic TPN and multiple admissions for pain crises and bowel obstruction. He was elected to undergo surgical intervention due to deteriorating quality of life and failure to thrive. Surgical management included an exploratory laparotomy with extensive lysis of adhesions (LOA), repair of gastrocutaneous fistula, and end ileostomy with Hartmann's pouch. Postoperative imaging confirmed resolution of the SBO, and the patient was transitioned to NGT feeds and eventually only PO intake. He is continuing with PO nutrition, gaining weight, and free from dialysis. Surgical intervention with LOA and release of small intestine can be successful for definitive management of EPS in the proper setting. In cases such as this, where management with enteral nutrition fails secondary to ongoing obstructive episodes, surgical intervention can be pursued in the interest of preserving quality of life.

Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE).

PubMed

Benson, Curtis; Paylor, John W; Tenorio, Gustavo; Winship, Ian; Baker, Glen; Kerr, Bradley J

2015-09-01

Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Knowledge-based computational intelligence development for predicting protein secondary structures from sequences.

PubMed

Shen, Hong-Bin; Yi, Dong-Liang; Yao, Li-Xiu; Yang, Jie; Chou, Kuo-Chen

2008-10-01

In the postgenomic age, with the avalanche of protein sequences generated and relatively slow progress in determining their structures by experiments, it is important to develop automated methods to predict the structure of a protein from its sequence. The membrane proteins are a special group in the protein family that accounts for approximately 30% of all proteins; however, solved membrane protein structures only represent less than 1% of known protein structures to date. Although a great success has been achieved for developing computational intelligence techniques to predict secondary structures in both globular and membrane proteins, there is still much challenging work in this regard. In this review article, we firstly summarize the recent progress of automation methodology development in predicting protein secondary structures, especially in membrane proteins; we will then give some future directions in this research field.

Progression of coronary artery calcification in black and white women: do the stresses and rewards of multiple roles matter?

PubMed

Janssen, Imke; Powell, Lynda H; Jasielec, Mateusz S; Matthews, Karen A; Hollenberg, Steven M; Sutton-Tyrrell, Kim; Everson-Rose, Susan A

2012-02-01

Black women experience higher rates of cardiovascular disease (CVD) than white women, though evidence for racial differences in subclinical CVD is mixed. Few studies have examined multiple roles (number, perceived stress, and/or reward) in relation to subclinical CVD, or whether those effects differ by race. The aim of this study was to investigate the effects of multiple roles on 2-year progression of coronary artery calcium. Subjects were 104 black and 232 white women (mean age 50.8 years). Stress and reward from four roles (spouse, parent, employee, caregiver) were assessed on five-point scales. Coronary artery calcium progression was defined as an increase of ≥10 Agatston units. White women reported higher rewards from their multiple roles than black women, yet black women showed cardiovascular benefits from role rewards. Among black women only, higher role rewards were related significantly to lower progression of coronary artery calcium, adjusting for body mass index, blood pressure, and other known CVD risk factors. Blacks reported fewer roles but similar role stress as whites; role number and stress were unrelated to coronary artery calcium progression. Rewarding roles may be a novel protective psychosocial factor for progression of coronary calcium among black women.

Validating Proposed Learning Progressions on Force and Motion Using the Force Concept Inventory: Findings from Singapore Secondary Schools

ERIC Educational Resources Information Center

Fulmer, Gavin W.

2015-01-01

This study examines the validity of 2 proposed learning progressions on the force concept when tested using items from the Force Concept Inventory (FCI). This is the first study to compare students' performance with respect to learning progressions both for force and motion and for Newton's third law in parallel. It is also among the first studies…

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.

Comparison between acute kidney injury (AKI) and non-AKI patients secondary to severe hypothyroidism.

PubMed

Han, Bing; Cheng, Tong; Ye, Lin; Sui, Chunhua; Yang, Lizhen; Lin, Dongping; Qiao, Jie; Lu, Yingli

2018-06-01

Hypothyroidism was a rare cause of rhabdomyolysis, which finally progressed to acute kidney injury (AKI). We compared nine patients with AKI secondary to hypothyroidism and six patients with severe hypothyroidism. Besides creatine kinase, globulin could be an alternative biomarker of rhabdomyolysis related to hypothyroidism.

Educational Reform and the World of Work: France. Reforms at the First Level of Secondary School

ERIC Educational Resources Information Center

Western European Education, 1977

1977-01-01

Investigates the effect of technical progress on educational reform in France. Factors considered include the lengthening of compulsory schooling, introduction of guidance and counseling facilities, vocational education reforms, and introduction of technology as a subject in the secondary school curriculum. (Author/DB)

Secondary School Transition: Planning for Success.

ERIC Educational Resources Information Center

Hemphill, Rae

Parents of adolescents with attention deficit disorders are offered suggestions for easing the transition of their teen from elementary to secondary school. Careful scheduling of classes with the guidance counselor to "fit" the individual teen's needs is urged. The importance of ongoing communication with the school concerning class progress,…

Drinking, Socioemotional Functioning, and Academic Progress in Secondary School

ERIC Educational Resources Information Center

Crosnoe, Robert; Benner, Aprile D.; Schneider, Barbara

2012-01-01

Secondary schools are sites of academic instruction but also contexts of socioemotional development, and the intertwining of these two functions has consequences for adolescents' future health and education. Drawing on nationally representative data from the National Longitudinal Study of Adolescent Health (n = 8,271), this study explored the…

Autistic Spectrum Disorders and Primary-Secondary Transition

ERIC Educational Resources Information Center

Jindal-Snape, D.; Douglas, W.; Topping, K. J.; Kerr, C.; Smith, E. F.

2006-01-01

Transition from primary to secondary school has been a focus of concern regarding pupil anxiety, social integration, lack of progression and under-achievement, particularly for children/young people with special educational needs (SEN). Previous studies often over-depended on data from professionals and treated all SEN as similar. This study…

Advantages of Integrative Data Analysis for Developmental Research

ERIC Educational Resources Information Center

Bainter, Sierra A.; Curran, Patrick J.

2015-01-01

Amid recent progress in cognitive development research, high-quality data resources are accumulating, and data sharing and secondary data analysis are becoming increasingly valuable tools. Integrative data analysis (IDA) is an exciting analytical framework that can enhance secondary data analysis in powerful ways. IDA pools item-level data across…

Continental Drift: A Discussion Strategy for Secondary School

ERIC Educational Resources Information Center

Paixao, Isabel; Calado, Silvia; Ferreira, Silvia; Salves, Vanda; Smorais, Ana M.

2004-01-01

The paper describes a discussion strategy for secondary school students. The strategy focus the various dimensions of Science, especially the internal sociological and philosophical dimensions. Students are expected to learn more about Science, namely the role of controversy for scientific progress. The article contains key questions for the…

FT-IR examination of the development of secondary cell wall in cotton fibers

USDA-ARS?s Scientific Manuscript database

The secondary cell wall development of cotton fibers harvested at 18, 20, 24, 28, 32, 36 and 40 days after flowering was examined using attenuated total reflection Fourier transform-infrared (ATR FT-IR) spectroscopy. Generally, a progressive intensity increase for bands assigned to cellulose Iß was ...

Early low-grade gastric MALToma rarely transforms into diffuse large cell lymphoma or progresses beyond the stomach and regional lymph nodes.

PubMed

Liu, Ting-Yun; Dei, Pei-Han; Kuo, Sung-Hsin; Lin, Chung-Wu

2010-06-01

Gastric mucosa-associated lymphoid tissue lymphoma (MALToma) usually presents at an early stage involving only the stomach and/or regional lymph nodes. Although a sequential transformation from low-grade gastric MALToma (GM) to high-grade GM to secondary diffuse large B-cell lymphoma (DLBCL) is commonly assumed, documented cases of transformation are rare. We aim to determine the frequency of transformation. We identified 55 early low-grade GMs, 18 early high-grade GMs, and 13 advanced GMs at the National Taiwan University Hospital from 1995 to 2005. The median follow-up time was 59 months. We found that only one early low-grade GM and two early high-grade GMs transformed into secondary DLBCLs and progressed outside the stomach and regional lymph nodes. Significantly, we identified 13 low-grade GMs that were refractory to Helicobacter eradication therapy or relapsed after initial response. All 13 cases had been followed-up for at least 3 years without development of secondary DLBCLs. The frequency of transformation for early low-grade GM was less than 2% (1/55). Although two lymphoma-unrelated mortalities were identified, none of the 55 patients with early-low grade GMs died of the disease. Compared with chronic lymphocytic leukemia, which has a 16% transformation rate and a median transformation time of 24 months, we conclude that early low-grade GM rarely transforms into secondary DLBCL or progresses beyond the stomach. Without transformation or progression, patients with early low-grade GM rarely die of the disease and should be treated conservatively. Copyright (c) 2010 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.

The Contributions of Primary and Secondary Memory to Working Memory Capacity: An Individual Differences Analysis of Immediate Free Recall

ERIC Educational Resources Information Center

Unsworth, Nash; Spillers, Gregory J.; Brewer, Gene A.

2010-01-01

The present study tested the dual-component model of working memory capacity (WMC) by examining estimates of primary memory and secondary memory from an immediate free recall task. Participants completed multiple measures of WMC and general intellectual ability as well as multiple trials of an immediate free recall task. It was demonstrated that…

Writing Development in Secondary/Post Secondary Language Learning: Integrating Multiple Motivating Factors, Explanatory Feedback, and Explanatory Writing Tools to Increase Competence and Confidence in Writing

ERIC Educational Resources Information Center

Jefferson, Trevina

2013-01-01

Background: This study discusses data-driven results of newly-developed writing tools that are objective, easy, and less time-consuming than standard classroom writing strategies; additionally, multiple motivation triggers and peer evaluation are evaluated together with these new, modernized writing tools. The results are explained separately and…

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.

Fluid Distribution Pattern in Adult-Onset Congenital, Idiopathic, and Secondary Normal-Pressure Hydrocephalus: Implications for Clinical Care.

PubMed

Yamada, Shigeki; Ishikawa, Masatsune; Yamamoto, Kazuo

2017-01-01

In spite of growing evidence of idiopathic normal-pressure hydrocephalus (NPH), a viewpoint about clinical care for idiopathic NPH is still controversial. A continuous divergence of viewpoints might be due to confusing classifications of idiopathic and adult-onset congenital NPH. To elucidate the classification of NPH, we propose that adult-onset congenital NPH should be explicitly distinguished from idiopathic and secondary NPH. On the basis of conventional CT scan or MRI, idiopathic NPH was defined as narrow sulci at the high convexity in concurrent with enlargement of the ventricles, basal cistern and Sylvian fissure, whereas adult-onset congenital NPH was defined as huge ventricles without high-convexity tightness. We compared clinical characteristics and cerebrospinal fluid distribution among 85 patients diagnosed with idiopathic NPH, 17 patients with secondary NPH, and 7 patients with adult-onset congenital NPH. All patients underwent 3-T MRI examinations and tap-tests. The volumes of ventricles and subarachnoid spaces were measured using a 3D workstation based on T2-weighted 3D sequences. The mean intracranial volume for the patients with adult-onset congenital NPH was almost 100 mL larger than the volumes for patients with idiopathic and secondary NPH. Compared with the patients with idiopathic or secondary NPH, patients with adult-onset congenital NPH exhibited larger ventricles but normal sized subarachnoid spaces. The mean volume ratio of the high-convexity subarachnoid space was significantly less in idiopathic NPH than in adult-onset congenital NPH, whereas the mean volume ratio of the basal cistern and Sylvian fissure in idiopathic NPH was >2 times larger than that in adult-onset congenital NPH. The symptoms of gait disturbance, cognitive impairment, and urinary incontinence in patients with adult-onset congenital NPH tended to progress more slowly compared to their progress in patients with idiopathic NPH. Cerebrospinal fluid distributions and disease progression were significantly different among the patients with adult-onset congenital NPH, idiopathic NPH and secondary NPH. This finding indicates that the pathogenesis of adult-onset congenital NPH may differ from those of idiopathic and secondary NPH. Therefore, adult-onset congenital NPH should be definitively distinguished from the categories of idiopathic and secondary NPH.

Effects of Coralliophila violacea on tissue loss in the scleractinian corals Porites spp. depend on host response

USGS Publications Warehouse

Raymundo, L.; Work, Thierry M.; Miller, R.L.; Lozada-Misa, P.L.

2016-01-01

We investigated interactions between the corallivorous gastropod Coralliophila violacea and its preferred hosts Porites spp. Our objectives were to experimentally determine whether tissue loss could progress in Porites during or after Coralliophila predation on corals with and without tissue loss and to histologically document snail predation. In 64% of feeding scars, tissue regenerated within 3 wk, leaving no trace of predation. However, in roughly 28% of scars, lesions progressed to subacute tissue loss resembling white syndrome. In feeding experiments, scars from snails previously fed diseased tissue developed progressive tissue loss twice as frequently as scars from snails previously fed healthy tissue. Scars from previously healthy-fed snails were 3 times as likely to heal as those from previously diseased-fed snails. Histology revealed marked differences in host responses to snails; P. cylindrica manifested a robust inflammatory response with fewer secondary colonizing organisms such as algae, sponges, and helminths, whereas P. rus showed no evident inflammation and more secondary colonization. We conclude that lesion progression associated with Coralliophila may be associated with secondary colonization of coral tissues damaged by predator-induced trauma and necrosis. Importantly, variation at the cellular level should be considered when explaining interspecific differences in host responses in corals impacted by phenomena such as predation.

Developing Learning Progression-Based Teacher Knowledge Measures

ERIC Educational Resources Information Center

Jin, Hui; Shin, HyoJeong; Johnson, Michele E.; Kim, JinHo; Anderson, Charles W.

2015-01-01

This study developed learning progression-based measures of science teachers' content knowledge (CK) and pedagogical content knowledge (PCK). The measures focus on an important topic in secondary science curriculum using scientific reasoning (i.e., tracing matter, tracing energy, and connecting scales) to explain plants gaining weight and…

Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

DTIC Science & Technology

2015-02-01

Athletes in contact sports who have sustained multiple concussive traumatic brain injuries are at high risk for delayed, progressive neurological and...11 or ‘punch drunk’ syndrome 9, 12. US military personnel 13, 14 and others who have sustained multiple concussive traumatic brain injuries 15-17...To date, none of the attempts to model progressive tau pathology after repetitive concussive TBI in mice has been optimal. Ongoing efforts include

Long-term disability progression in primary progressive multiple sclerosis: a 15-year study.

PubMed

Rocca, Maria A; Sormani, Maria Pia; Rovaris, Marco; Caputo, Domenico; Ghezzi, Angelo; Montanari, Enrico; Bertolotto, Antonio; Laroni, Alice; Bergamaschi, Roberto; Martinelli, Vittorio; Comi, Giancarlo; Filippi, Massimo

2017-11-01

Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Kenya's Constituency Development Fund, Free Secondary Education Policy, and Access to Secondary Education

ERIC Educational Resources Information Center

Nzuki, Charles Kyalo

2018-01-01

The effects of the Constituency Development Fund (CDF) and the Free Secondary Education Policy (FSEP) on access to secondary school education in Kenya's Yatta sub-county have not been adequately explored in available public policy literature. Hence, this qualitative multiple-case study was designed to understand the effects of the 2 policies on…

Resonance transition periodic orbits in the circular restricted three-body problem

NASA Astrophysics Data System (ADS)

Lei, Hanlun; Xu, Bo

2018-04-01

This work studies a special type of cislunar periodic orbits in the circular restricted three-body problem called resonance transition periodic orbits, which switch between different resonances and revolve about the secondary with multiple loops during one period. In the practical computation, families of multiple periodic orbits are identified first, and then the invariant manifolds emanating from the unstable multiple periodic orbits are taken to generate resonant homoclinic connections, which are used to determine the initial guesses for computing the desired periodic orbits by means of multiple-shooting scheme. The obtained periodic orbits have potential applications for the missions requiring long-term continuous observation of the secondary and tour missions in a multi-body environment.

[External progressive ophthalmoplegia secondary to mitochondrial myopathy. Report of a case and review of the literature].

PubMed

Calderón-Garcidueñas, A L; Pérez-Loria, O; Alberto-Sagástegui, J; Farías-García, R

2000-01-01

Progressive limitation of occular motility, accompanied by ptosis but usually without diplopia, occurs in many pathologic states, including mitochondrial diseases. A case with chronic progressive external ophthalmoplegia with onset during childhood, associated with proximal myopathy and dysphasia is presented. The muscle biopsy showed a myopathic pattern and abnormal subsarcolemmal mitochondrial deposits. Muscle biopsy for important in the correct diagnosis of this entity.

[A case of fulminant hepatic failure secondary to hepatic metastasis of small cell lung carcinoma].

PubMed

Hwang, Young Tae; Shin, Jung Woo; Lee, Jun Ho; Hwang, Dae Sung; Eum, Jun Bum; Choi, Hye Jeong; Park, Neung Hwa

2007-12-01

Although liver metastasis is commonly found in cancer patients, fulminant hepatic failure secondary to diffuse cancer infiltration into the liver is rare. Liver metastasis-induced fulminant hepatic failure has been reported in patients with primary cancer of the gastrointestinal tract, breast and uroepithelium, and in patients with melanoma and hematologic malignancy. Small cell lung cancer is so highly invasive that hepatic metastasis is common, but rapid progression to fulminant hepatic failure is extremely rare. We report here on a case of a patient who died because of rapid progression to fulminant hepatic failure as a result of hepatic metastasis of small cell lung carcinoma.

New secondary batteries utilizing electronically conductive polymer cathodes

NASA Technical Reports Server (NTRS)

Martin, Charles R.; White, Ralph E.

1989-01-01

The objectives of this project are to characterize the transport properties in electronically conductive polymers and to assess the utility of these films as cathodes in lithium/polymer secondary batteries. During this research period, progress has been made in a literature survey of the historical background, methods of preparation, the physical and chemical properties, and potential technological applications of polythiophene. Progress has also been made in the characterization of polypyrrole flat films and fibrillar films. Cyclic voltammetry and potential step chronocoulometry were used to gain information on peak currents and potentials switching reaction rates, charge capacity, and charge retention. Battery charge/discharge studies were also performed.

34 CFR 200.14 - Components of Adequate Yearly Progress.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Components of Adequate Yearly Progress. 200.14 Section 200.14 Education Regulations of the Offices of the Department of Education OFFICE OF ELEMENTARY AND SECONDARY EDUCATION, DEPARTMENT OF EDUCATION TITLE I-IMPROVING THE ACADEMIC ACHIEVEMENT OF THE DISADVANTAGED...

Teaching Multi-Level Classes: A Lesson from the Past.

ERIC Educational Resources Information Center

Book, Leon C.

The laboratory school for Southeast Missouri State University offers individualized French and Spanish second language instruction to secondary students by scheduling them together in one multilevel class. Students progress individually and in small groups through planned, self-paced, continuous progress programs. Each student is given a checklist…

Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo.

PubMed

Havens, Aaron M; Sun, Hongli; Shiozawa, Yusuke; Jung, Younghun; Wang, Jingcheng; Mishra, Anjali; Jiang, Yajuan; O'Neill, David W; Krebsbach, Paul H; Rodgerson, Denis O; Taichman, Russell S

2014-04-01

The purpose of this study was to determine the lineage progression of human and murine very small embryonic-like (HuVSEL or MuVSEL) cells in vitro and in vivo. In vitro, HuVSEL and MuVSEL cells differentiated into cells of all three embryonic germ layers. HuVSEL cells produced robust mineralized tissue of human origin compared with controls in calvarial defects. Immunohistochemistry demonstrated that the HuVSEL cells gave rise to neurons, adipocytes, chondrocytes, and osteoblasts within the calvarial defects. MuVSEL cells were also able to differentiate into similar lineages. First round serial transplants of MuVSEL cells into irradiated osseous sites demonstrated that ∼60% of the cells maintained their VSEL cell phenotype while other cells differentiated into multiple tissues at 3 months. Secondary transplants did not identify donor VSEL cells, suggesting limited self renewal but did demonstrate VSEL cell derivatives in situ for up to 1 year. At no point were teratomas identified. These studies show that VSEL cells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-based regenerative therapies for osseous, neural, and connective tissue disorders.

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.

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.

Multiple-Coil, Pulse-Induction Metal Detector

NASA Technical Reports Server (NTRS)

Lesky, Edward S.; Reid, Alan M.; Bushong, Wilton E.; Dickey, Duane P.

1988-01-01

Multiple-head, pulse-induction metal detector scans area of 72 feet squared with combination of eight detector heads, each 3 ft. square. Head includes large primary coil inducing current in smaller secondary coils. Array of eight heads enables searcher to cover large area quickly. Pulses applied to primary coil, induced in secondary coils measured to determine whether metal present within range of detector head. Detector designed for recovery of Space Shuttle debris.

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study.

PubMed

Chang, Su-Hsin; Luo, Suhong; O'Brian, Katiuscia K; Thomas, Theodore S; Colditz, Graham A; Carlsson, Nils P; Carson, Kenneth R

2015-01-01

Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49–96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25–0·87). For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.

Association of the Philadelphia chromosome and 5q- in secondary blood disorder

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

Dastugue, N.; Demur, C.; Pris, F.

1988-02-01

A patient developed a secondary blood disorder 7 years after radiotherapy for a gastric lymphoma. The initial myelodysplastic syndrome evolved to a myeloproliferative phase with transient polycythemia, progressive thrombocythemia, and hyperleukocytosis. Chromosome analysis performed in the terminal phase showed del(5)(q13q31),t(9;22)(q34;q11), and a complex rearrangement involving chromosomes number2 and number3. A correlation between chromosomal abnormalities and hematologic findings could be established. In this case, we have assumed that the Philadelphia translocation is a late event, due to prior mutagen exposure, and its association with a common secondary abnormality (5q-), followed by a progressively developing myeloproliferative phase. Furthermore, the association of Phmore » and 5q- in a single clone seems to indicate that the same stem cell is affected by these two abnormalities.« less

Endoscopic Endonasal Approach in Skull Base Chondrosarcoma Associated with Maffucci Syndrome: Case Series and Literature Review.

PubMed

Beer-Furlan, André; Balsalobre, Leonardo; Vellutini, Eduardo A S; Stamm, Aldo C

2016-01-01

Maffucci syndrome is a nonhereditary disorder in which patients develop multiple enchondromas and cutaneous, visceral, or soft tissue hemangiomas. The potential malignant progression of enchondroma into a secondary chondrosarcoma is a well-known fact. Nevertheless, chondrosarcoma located at the skull base in patients with Maffuci syndrome is a very rare condition, with only 18 cases reported in the literature. We report 2 other cases successfully treated through an expanded endoscopic endonasal approach and discuss the condition based on the literature review. Skull base chondrosarcoma associated with Maffucci syndrome is a rare condition. The disease cannot be cured, therefore surgical treatment should be performed in symptomatic patients aiming for maximal tumor resection with function preservation. The endoscopic endonasal approach is a safe and reliable alternative for the management of these tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Enucleation in a Cownose Ray (Rhinoptera bonasus)

PubMed Central

Yee-Nin, S. T.; Hassan, H. M. D.; Wahid, A. H.

2018-01-01

Trauma is a common problem in Cownose Ray during mating season in both wild and captive rays. Enucleation is indicated when there is an ocular trauma. A 5-year-old female Cownose Ray (Rhinoptera bonasus) from Aquaria of Kuala Lumpur Convention Centre (KLCC) was presented to University Veterinary Hospital (UVH), Universiti Putra Malaysia, with a complaint of protruding left eye, which resulted from crushing into artificial coral during mating season. There were a hyphema in the traumatic left eye, periorbital tissue tear, exposed left eye socket, and multiple abrasions on both pectoral fins. The Cownose was anaesthetized and maintained with isoeugenol and on-field emergency enucleation of the left eye was performed. It was managed medically with postoperative enrofloxacin, tobramycin ointment, and povidone iodine. No suture breakdown and secondary infection were observed at day 7 after enucleation during revisit. At day 24 after enucleation, the Cownose responded well to treatment with excellent healing progression and no surgical complication was observed.

The Validity of Dependence as a Health Outcome Measure in Alzheimer’s Disease

PubMed Central

Spackman, D. Eldon; Kadiyala, Srikanth; Neumann, Peter J.; Veenstra, David L.; Sullivan, Sean D.

2013-01-01

Background Relating to Alzheimer’s disease (AD), dependence has been defined as the increased need for assistance due to deterioration in cognition, physical functioning, and behavior. Our objective was to evaluate the association between dependence and measures of functional impairment. Methods Data were compiled by the National Alzheimer’s Coordinating Center. We used multinomial logistic regression to estimate the association between dependence and cognition, physical functioning, and behavior. Results The independent association with dependence was positive. Dependence was most strongly associated with physical functioning. A secondary analysis suggested a strong association of dependence with multiple impairments, as measured by the interaction terms, in more severe patients. Conclusions We find that dependence is simultaneously associated with physical functioning, cognition, and behavior, which support the construct validity of dependence. Dependence might be a more simple measure to explain the multifaceted disease progression of AD and convey the increasing need for care. PMID:23512996

The validity of dependence as a health outcome measure in Alzheimer's disease.

PubMed

Spackman, D Eldon; Kadiyala, Srikanth; Neumann, Peter J; Veenstra, David L; Sullivan, Sean D

2013-05-01

Relating to Alzheimer's disease (AD), dependence has been defined as the increased need for assistance due to deterioration in cognition, physical functioning, and behavior. Our objective was to evaluate the association between dependence and measures of functional impairment. Data were compiled by the National Alzheimer's Coordinating Center. We used multinomial logistic regression to estimate the association between dependence and cognition, physical functioning, and behavior. The independent association with dependence was positive. Dependence was most strongly associated with physical functioning. A secondary analysis suggested a strong association of dependence with multiple impairments, as measured by the interaction terms, in more severe patients. We find that dependence is simultaneously associated with physical functioning, cognition, and behavior, which support the construct validity of dependence. Dependence might be a more simple measure to explain the multifaceted disease progression of AD and convey the increasing need for care.

Macrocytosis secondary to hydroxyurea therapy.

PubMed

Conrado, Francisco O; Weeden, Amy L; Speas, Abbie L; Leissinger, Mary K

2017-09-01

A 10-year-old, male neutered Shetland Sheepdog was presented to the University of Florida for evaluation of a well-granulated mast cell tumor. Hydroxyurea therapy was instituted and serial CBCs showed persistent mild anemia and macrocytosis without a corresponding increase in polychromasia. The dog's MCV increased progressively, reaching its highest value of 100.0 fL after 6 months of treatment, and a diagnosis of macrocytosis associated with hydroxyurea therapy was made. The dog's increase in MCV was prominent, and rapidly decreased after the drug was discontinued, consistent with previous observations in human and canine subjects treated with hydroxyurea. Hydroxyurea is a cytotoxic chemotherapeutic agent used in a variety of conditions in human and veterinary medicine, and megaloblastic changes associated with its use have been described in multiple species. This report shows that hydroxyurea treatment is a differential diagnosis for prominent macrocytosis in dogs in the absence of other signs of erythrocyte regeneration. © 2017 American Society for Veterinary Clinical Pathology.

Minimally invasive palliative resection of lumbar epidural metastasis.

PubMed

Yew, Andrew; Kimball, Jon; Pezeshkian, Patrick; Lu, Daniel C

2013-07-01

Spinal metastatic lesions are the most common tumors encountered by spinal surgeons. As with procedures for degenerative disease, minimally invsive surgery techniques have been applied to minimize muscle and soft tissue destruction in procedures for tumor resection. Here, we present a 23-year-old female with radiculopathy and foot drop secondary to nerve root compression by epidural metastases from Ewing's sarcoma. This patient had a history of previous resection and instrumentation as well as multiple rounds of chemotherapy and radiation that failed to control her disease. The patient presented with three weeks of radicular pain and foot drop that was continuing to worsen at the time of her operation. The decision was therefore made to perform a palliative resection and decompression for relief of her progressive symptoms. In this video, we demonstrate a palliative tumor debulking and nerve root decompression utilizing an MIS approach. The video can be found here: http://youtu.be/tq4kbvKTebI.

Traumatic brain injury: a risk factor for neurodegenerative diseases.

PubMed

Gupta, Rajaneesh; Sen, Nilkantha

2016-01-01

Traumatic brain injury (TBI), a major global health and socioeconomic problem, is now established as a chronic disease process with a broad spectrum of pathophysiological symptoms followed by long-term disabilities. It triggers multiple and multidirectional biochemical events that lead to neurodegeneration and cognitive impairment. Recent studies have presented strong evidence that patients with TBI history have a tendency to develop proteinopathy, which is the pathophysiological feature of neurodegenerative disorders such as Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). This review mainly focuses on mechanisms related to AD, CTE, and ALS that are induced after TBI and their relevance to the advancement of these neurodegenerative diseases. This review encompasses acute effects and chronic neurodegenerative consequences after TBI for a better understanding of TBI-induced neuronal death and to design therapies that will effectively treat patients in the primary or secondary progressive stages.

A Conceptual Framework for Addressing Residual Atherosclerotic Cardiovascular Disease Risk in the Era of Precision Medicine.

PubMed

Patel, Kershaw V; Pandey, Ambarish; de Lemos, James A

2018-04-11

Until recently, therapies to mitigate atherosclerotic cardiovascular disease (ASCVD) risk have been limited to lifestyle interventions, blood pressure lowering medications, high intensity statin therapy, antiplatelet agents, and in select patients, coronary artery revascularization. Despite administration of these evidence-based therapies, substantial residual risk for cardiovascular events persists, particularly among individuals with known ASCVD. Moreover, the current guideline-based approach does not adequately account for patient-specific, causal pathways that lead to ASCVD progression and complications. In the past few years, multiple new pharmacological agents, targeting conceptually distinct pathophysiological targets, have been shown in large and well-conducted clinical trials to lower cardiovascular risk among patients with established ASCVD receiving guideline directed medical care. These evidenced-based therapies reduce event rates, and in some cases all-cause and cardiovascular mortality; these benefits confirm important new disease targets and challenge the adequacy of the current "standard of care" for secondary prevention.

[Primary and secondary encopresis].

PubMed

Lang-Langer, Ellen

2007-01-01

While the difficulty of the child to part with its faeces in primary encopresis is linked to the incapability to experience the object as separated and independent from himself, secondary encopresis is a progressed psychical state of development. In this case we have to deal with regression caused by conflict. Two case-studies show clearly the differences.

Secondary metabolite profiles of leaves of healthy and huanglongbing-infected orange (Citrus sinensis L.) seedlings measured by HPLC-fluorescence detection

USDA-ARS?s Scientific Manuscript database

Leaves of greenhouse-grown ‘Hamlin’ and ‘Valencia’ orange (Citrus sinensis L.) seedlings were analyzed by high performance liquid chromatography in a study of the progression of changes in secondary metabolite profiles resulting from infection by Candidatus Liberibacter asiaticus (CLas), the Huanglo...

A Study on Academic Achievement and Personality of Secondary School Students

ERIC Educational Resources Information Center

Suvarna, V. D.; Ganesha Bhata, H. S.

2016-01-01

This study is concerned with the Academic Achievement and Personality of 300 students of secondary schools of Mandya city. The Raven's Standard Progress Matrices was used to obtain the Academic Scores and Eysenk Personality Inventory was used to collect data regarding their Personality. Result reflects that there is negligible positive…

Why Secondary Teachers Fail Students.

ERIC Educational Resources Information Center

Ligon, Glynn; Jackson, Elaine E.

The perceptions of teachers about students' lack of success were studied, and the groundwork was laid for the future study of the effectiveness of a policy of warning students and parents of impending failure. The primary sources of data were teacher-coded reasons for failure, given on notices (progress reports) to secondary school students in the…

Teaching Balance with Tai Chi: Strategies for College and Secondary School Instruction.

ERIC Educational Resources Information Center

Chen, David D.; Sherman, Clay P.

2002-01-01

Examines the benefits of incorporating Tai Chi into the secondary and college curriculum to teach balance, discussing: the history and philosophical underpinnings of Tai Chi, principles of Tai Chi movement, health benefits, and teaching Tai Chi in public schools. Tips for instructors include: follow the principles of progression, follow a…

Secondary cell wall development in cotton fibers as examined with attenuated total reflection Fourier transform infrared spectroscopy

USDA-ARS?s Scientific Manuscript database

Cotton fibers harvested at 18, 20, 24, 28, 32, 36 and 40 days after flowering were examined using attenuated total reflection Fourier transform-infrared (ATR FT-IR) spectroscopy. The selected harvesting points coincide with secondary cell wall (SCW) development in the fibers. Progressive but moderat...

High School Students' Knowledge of a Square as a Basis for Developing a Geometric Learning Progression

ERIC Educational Resources Information Center

Seah, Rebecca; Horne, Marj; Berenger, Adrian

2016-01-01

This study surveyed and analysed four secondary school students' writing about a square. Sfard's discursive approach to understanding mathematical discourse was used to analyse the responses collected from 214 Australian secondary school students. The results showed that geometric knowledge was developed experientially and not developmentally.…

Plan for Progress in the Media Center; 7-12.

ERIC Educational Resources Information Center

Iowa State Dept. of Public Instruction, Des Moines.

This handbook has been prepared by a committee composed of administrators and media specialists under the direction of the Department of Public Instruction. Its purpose is to establish guidelines for media centers in the secondary schools of Iowa. Most secondary schools in Iowa now have traditional libraries. This handbook provides guidelines for…

Physical activity in primary and secondary prevention of cardiovascular disease: Overview updated.

PubMed

Alves, Alberto J; Viana, João L; Cavalcante, Suiane L; Oliveira, Nórton L; Duarte, José A; Mota, Jorge; Oliveira, José; Ribeiro, Fernando

2016-10-26

Although the observed progress in the cardiovascular disease treatment, the incidence of new and recurrent coronary artery disease remains elevated and constitutes the leading cause of death in the developed countries. Three-quarters of deaths due to cardiovascular diseases could be prevented with adequate changes in lifestyle, including increased daily physical activity. New evidence confirms that there is an inverse dose-response relationship between physical activity and cardiovascular disease and mortality risk. However, participation in moderate to vigorous physical activity may not fully attenuate the independent effect of sedentary activities on increased risk for cardiovascular diseases. Physical activity also plays an important role in secondary prevention of cardiovascular diseases by reducing the impact of the disease, slowing its progress and preventing recurrence. Nonetheless, most of eligible cardiovascular patients still do not benefit from secondary prevention/cardiac rehabilitation programs. The present review draws attention to the importance of physical activity in the primary and secondary prevention of cardiovascular diseases. It also addresses the mechanisms by which physical activity and regular exercise can improve cardiovascular health and reduce the burden of the disease.

Glomerulonephritis

MedlinePlus

... glomerulonephritis; Glomerulonephritis - crescentic; Crescentic glomerulonephritis; Rapidly progressive glomerulonephritis Images Kidney anatomy References Appel GB, Radhakrishnan J, D'Agati V. Secondary glomerular disease. In: Skorecki ...

The multiple imputation method: a case study involving secondary data analysis.

PubMed

Walani, Salimah R; Cleland, Charles M

2015-05-01

To illustrate with the example of a secondary data analysis study the use of the multiple imputation method to replace missing data. Most large public datasets have missing data, which need to be handled by researchers conducting secondary data analysis studies. Multiple imputation is a technique widely used to replace missing values while preserving the sample size and sampling variability of the data. The 2004 National Sample Survey of Registered Nurses. The authors created a model to impute missing values using the chained equation method. They used imputation diagnostics procedures and conducted regression analysis of imputed data to determine the differences between the log hourly wages of internationally educated and US-educated registered nurses. The authors used multiple imputation procedures to replace missing values in a large dataset with 29,059 observations. Five multiple imputed datasets were created. Imputation diagnostics using time series and density plots showed that imputation was successful. The authors also present an example of the use of multiple imputed datasets to conduct regression analysis to answer a substantive research question. Multiple imputation is a powerful technique for imputing missing values in large datasets while preserving the sample size and variance of the data. Even though the chained equation method involves complex statistical computations, recent innovations in software and computation have made it possible for researchers to conduct this technique on large datasets. The authors recommend nurse researchers use multiple imputation methods for handling missing data to improve the statistical power and external validity of their studies.

A zebrafish model of diabetes mellitus and metabolic memory.

PubMed

Intine, Robert V; Olsen, Ansgar S; Sarras, Michael P

2013-02-28

Diabetes mellitus currently affects 346 million individuals and this is projected to increase to 400 million by 2030. Evidence from both the laboratory and large scale clinical trials has revealed that diabetic complications progress unimpeded via the phenomenon of metabolic memory even when glycemic control is pharmaceutically achieved. Gene expression can be stably altered through epigenetic changes which not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters once the stimulus is removed. As such, the roles that these mechanisms play in the metabolic memory phenomenon are currently being examined. We have recently reported the development of a zebrafish model of type I diabetes mellitus and characterized this model to show that diabetic zebrafish not only display the known secondary complications including the changes associated with diabetic retinopathy, diabetic nephropathy and impaired wound healing but also exhibit impaired caudal fin regeneration. This model is unique in that the zebrafish is capable to regenerate its damaged pancreas and restore a euglycemic state similar to what would be expected in post-transplant human patients. Moreover, multiple rounds of caudal fin amputation allow for the separation and study of pure epigenetic effects in an in vivo system without potential complicating factors from the previous diabetic state. Although euglycemia is achieved following pancreatic regeneration, the diabetic secondary complication of fin regeneration and skin wound healing persists indefinitely. In the case of impaired fin regeneration, this pathology is retained even after multiple rounds of fin regeneration in the daughter fin tissues. These observations point to an underlying epigenetic process existing in the metabolic memory state. Here we present the methods needed to successfully generate the diabetic and metabolic memory groups of fish and discuss the advantages of this model.

Upper Extremity Function in Multiple Sclerosis Patients With Advanced Disability Treated With Ocrevus

ClinicalTrials.gov

2018-06-18

Multiple Sclerosis; Pathologic Processes; Demyelinating Diseases; Demyelinating Autoimmune Diseases; Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Primary Progressive Multiple Sclerosis; Relapsing Remitting Multiple Sclerosis

Occupational Skills and Labour Market Progression of Married Immigrant Women in Canada

PubMed Central

Adserà, Alícia; Ferrer, Ana

2016-01-01

We use the confidential files of the 1991-2006 Canadian Census, combined with information from O*NET on the skill requirements of jobs, to explore whether immigrant women behave as secondary workers, remaining marginally attached to the labour market and experiencing little career progression over time. Our results show that the current labour market patterns of female immigrants to Canada do not fit this profile, as previous studies found, but rather conform to patterns recently exhibited by married native women elsewhere, with rising participation and wage progression. At best, only relatively uneducated immigrant women in unskilled occupations may fit the profile of secondary workers, with slow skill mobility and low-status job-traps. Educated immigrant women, on the other hand, experience skill assimilation over time: a reduction in physical strength and an increase in analytical skills required in their jobs relative to those of natives. PMID:27217617

The relationship between nutrition and prostate cancer: is more always better?

PubMed

Masko, Elizabeth M; Allott, Emma H; Freedland, Stephen J

2013-05-01

Prostate cancer (PCa) remains one of the most diagnosed malignancies in the world, correlating with regions where men consume more of a so-called Western-style diet. As such, there is much interest in understanding the role of lifestyle and diet on the incidence and progression of PCa. To provide a summary of published literature with regard to dietary macro- and micronutrients and PCa incidence and progression. A literature search was completed using the PubMed database for all studies published on diet and PCa in June 2012 or earlier. Primary literature and meta-analyses were given preference over other review articles when possible. The literature was reviewed on seven dietary components: carbohydrates, protein, fat and cholesterol, vegetables, vitamins and minerals, and phytochemicals. Current literature linking these nutrients to PCa is limited at best, but trends in the published data suggest consumption of carbohydrates, saturated and ω-6 fats, and certain vitamin supplements may promote PCa risk and progression. Conversely, consumption of many plant phytochemicals and ω-3 fatty acids seem to slow the risk and progression of the disease. All other nutrients seem to have no effect or data are inconclusive. A brief summary about the clinical implications of dietary interventions with respect to PCa prevention, treatment, and survivorship is provided. Due to the number and heterogeneity of published studies investigating diet and PCa, it is difficult to determine what nutrients make up the perfect diet for the primary and secondary prevention of PCa. Because diets are made of multiple macro- and micronutrients, further prospective studies are warranted, particularly those investigating the relationship between whole foods instead of a single nutritional component. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Sequential karyotyping in Burkitt lymphoma reveals a linear clonal evolution with increase in karyotype complexity and a high frequency of recurrent secondary aberrations.

PubMed

Aukema, Sietse M; Theil, Laura; Rohde, Marius; Bauer, Benedikt; Bradtke, Jutta; Burkhardt, Birgit; Bonn, Bettina R; Claviez, Alexander; Gattenlöhner, Stefan; Makarova, Olga; Nagel, Inga; Oschlies, Ilske; Pott, Christiane; Szczepanowski, Monika; Traulsen, Arne; Kluin, Philip M; Klapper, Wolfram; Siebert, Reiner; Murga Penas, Eva M

2015-09-01

Typical Burkitt lymphoma is characterized by an IG-MYC translocation and overall low genomic complexity. Clinically, Burkitt lymphoma has a favourable prognosis with very few relapses. However, the few patients experiencing disease progression and/or relapse have a dismal outcome. Here we report cytogenetic findings of seven cases of Burkitt lymphoma in which sequential karyotyping was performed at time of diagnosis and/or disease progression/relapse(s). After case selection, karyotype re-review and additional molecular analyses were performed in six paediatric cases, treated in Berlin-Frankfurt-Münster-Non-Hodgkin lymphoma study group trials, and one additional adult patient. Moreover, we analysed 18 cases of Burkitt lymphoma from the Mitelman database in which sequential karyotyping was performed. Our findings show secondary karyotypes to have a significant increase in load of cytogenetic aberrations with a mean number of 2, 5 and 8 aberrations for primary, secondary and third investigations. Importantly, this increase in karyotype complexity seemed to result from recurrent secondary chromosomal changes involving mainly trisomy 21, gains of 1q and 7q, losses of 6q, 11q, 13q, and 17p. In addition, our findings indicate a linear clonal evolution to be the predominant manner of cytogenetic evolution. Our data may provide a biological framework for the dismal outcome of progressive and relapsing Burkitt lymphoma. © 2015 John Wiley & Sons Ltd.

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

PubMed

Chevalier, Julie; Chamoux, Catherine; Hammès, Florence; Chicoye, Annie

2016-01-01

The paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015. The economic model was adapted to the French setting in accordance with the Haute Autorité de Santé guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0-9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0-9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results. From both perspectives, dimethyl fumarate and interferon beta-1a (IFN beta-1a) 44 mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30 mcg, IFN beta-1b 250 mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44 mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY. Despite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier.

Monitoring My Multiple Sclerosis

PubMed Central

Namey, Marie; Halper, June

2011-01-01

Optimal health of people with multiple sclerosis (MS) can be promoted by patients' sharing of health information gained through periodic self-monitoring with their health-care providers. The purpose of this study was to develop a valid and reliable self-administered scale to obtain information about MS patients' health status and the impact of the disease on their daily lives. We named this scale “Monitoring My Multiple Sclerosis” (MMMS). A cross-sectional survey was conducted of 171 MS patients who completed the MMMS and Patient-Determined Disease Steps (PDDS) scales and provided information on their MS disease classification and demographic characteristics. Data analysis included several parametric procedures. Factor analysis of the 26-item MMMS resulted in four factors with satisfactory α reliability coefficients for the total scale (0.90) and factored subscales: Physical (0.85), Relationships (0.80), Energy (0.70), and Cognitive/Mental (0.67). Analysis of variance demonstrated that the total scale and the Physical subscale, but not the Relationships subscale, showed significantly worse functioning for patients with either moderate or severe disability as measured by the PDDS than for patients with mild disability (P < .001). The Cognitive/Mental subscale showed significantly worse functioning for patients with moderate disability than for patients with mild disability (P < .05). However, the Energy subscale showed significantly worse functioning among moderately disabled patients than among severely disabled patients (P < .01). Independent t tests demonstrated that patients classified as having secondary progressive multiple sclerosis had significantly worse scores on the total MMMS (P < .05) and the Physical subscale (P < .001) than those classified as having relapsing-remitting multiple sclerosis. The MMMS demonstrated satisfactory reliability and validity and is recommended for use by MS patients and their health-care providers as a mechanism to promote the sharing of health information, to the benefit of both patients and providers. PMID:24453717

Utility of electrocardiogram in the assessment and monitoring of pulmonary hypertension (idiopathic or secondary to pulmonary developmental abnormalities) in patients≤18 years of age.

PubMed

Lau, Kelvin C; Frank, David B; Hanna, Brian D; Patel, Akash R

2014-07-15

Electrocardiograms have utility in disease stratification and monitoring in adult pulmonary arterial hypertension (PAH). We examined the electrocardiographic findings that are common in pediatric PAH and assessed for correlation with disease severity and progression. We retrospectively identified patients aged≤18 years followed at a single institution from January 2001 to June 2012 with catheterization-confirmed diagnosis of idiopathic PAH and PAH secondary to pulmonary developmental abnormalities. Patients with an electrocardiography performed within 60 days of catheterization were included. Primary and secondary outcomes are the prevalence of abnormal electrocardiographic findings at the time of catheterization and the association between electrocardiographic and hemodynamic findings and electrocardiographic changes with disease progression on follow-up catheterization, respectively. Of the 100 electrocardiography-catheterization pairs derived from the 46 patients identified, 93% had an electrocardiographic abnormality: 78% had right ventricular hypertrophy (RVH) and 52% had right axis deviation (RAD) for age. In patients with idiopathic PAH, the presence of RVH and RAD correlated with pulmonary vascular resistance and transpulmonary gradient. RAD and RVH on baseline electrocardiogram was associated with an increased risk of disease progression on subsequent catheterization (odds ratio 11.0, 95% confidence interval 1.3 to 96.2, p=0.03) after adjusting for PAH subgroup. The sensitivity, specificity, and positive and negative predictive values of RAD and RVH on baseline electrocardiogram for disease progression were 92%, 48%, 33%, and 95%, respectively. In conclusion, electrocardiographic abnormalities are common in pediatric PAH. RAD and RVH on electrocardiogram were associated with worse hemodynamics, whereas their absence is suggestive of a lack of disease progression. Copyright © 2014 Elsevier Inc. All rights reserved.

20 CFR 411.180 - What is timely progress toward self-supporting employment?

Code of Federal Regulations, 2010 CFR

2010-04-01

... certificate or vocational or technical training that will enhance your ability to return to work. In addition...-secondary education requirement or vocational or technical training requirement in the applicable progress... this 12-month period; or (iv) You must have been enrolled in a vocational or technical training program...

New Data, Old Tensions: Big Data, Personalized Learning, and the Challenges of Progressive Education

ERIC Educational Resources Information Center

Dishon, Gideon

2017-01-01

Personalized learning has become the most notable application of big data in primary and secondary schools in the United States. The combination of big data and adaptive technological platforms is heralded as a revolution that could transform education, overcoming the outdated classroom model, and realizing the progressive vision of…

Straight A's: Public Education Policy and Progress. Volume 10, Number 10

ERIC Educational Resources Information Center

Alliance for Excellent Education, 2010

2010-01-01

"Straight A's: Public Education Policy and Progress" is a biweekly newsletter that focuses on education news and events both in Washington, DC and around the country. The following articles are included in this issue: (1) ESEA [Elementary and Secondary Education Act] Reauthorization Shifts to Middle and High Schools: Senate HELP [Health,…

Progressive valgus angulation of the ankle secondary to loss of fibular congruity treated with medial tibial hemiepiphysiodesis and fibular reconstruction.

PubMed

Lesiak, Alex C; Esposito, Paul W

2014-06-01

The fibula is an important stabilizer of the lateral ankle. Discontinuity of the fibular shaft can lead to progressive pain and shortening of the fibula, ultimately causing loss of lateral support to the ankle. Two children, who sustained segmental bone loss of the shaft of the fibula, developed progressive symptomatic valgus of the ankle with widening of the mortice and lateral subluxation of the talus. Both patients were treated with fibular plating and grafting with tricalcium sulfate with acute reconstitution of fibular length. Distal medial tibial hemiepiphysiodesis was simultaneously performed. One patient required revision plating and grafting 14 months after the index surgery because of plate failure. The valgus angulation and the widened medial mortice were corrected in the ankles of both patients, who returned to full activities. The patients were followed to maturity; the correction has been maintained, and they remain asymptomatic. The technique used in these cases can correct valgus angulation secondary to loss of fibular congruity rather than only halting progression of the deformity.

Use of semiochemicals of secondary bark beetles to disrupt spruce beetle attraction and survival in Alaska.

Treesearch

Richard A. Werner; Edward H. Holsten

2002-01-01

Field experiments using baited multiple-funnel traps and baited felled trees were conducted to test the hypothesis that semiochemicals from secondary species of scolytids could be used to disrupt spruce beetle (Dendroctonus rufipennis (Kirby)) attraction. Semiochemicals from three secondary species of scolytids, (Ips perturbatus...

[Charles Darwin and the problem of evolutionary progress].

PubMed

Iordanskiĭ, N N

2010-01-01

According to Ch. Darwin's evolutionary theory, evolutionary progress (interpreted as morpho-physiological progress or arogenesis in recent terminology) is one of logical results of natural selection. At the same time, natural selection does not hold any factors especially promoting evolutionary progress. Darwin emphasized that the pattern of evolutionary changes depends on organism nature more than on the pattern of environment changes. Arogenesis specificity is determined by organization of rigorous biological systems - integral organisms. Onward progressive development is determined by fundamental features of living organisms: metabolism and homeostasis. The concept of social Darwinism differs fundamentally from Darwin's ideas about the most important role of social instincts in progress of mankind. Competition and selection play secondary role in socio-cultural progress of human society.

Analysis of selected social determinants of health and their relationships with maternal health service coverage and child mortality in Vietnam.

PubMed

Van Minh, Hoang; Giang, Kim Bao; Hoat, Luu Ngoc; Chung, Le Hong; Huong, Tran Thi Giang; Phuong, Nguyen Thi Kim; Valentine, Nicole B

2016-01-01

Achieving a fair and equitable distribution of health in the population while progressing toward universal health coverage (UHC) is a key focus of health policy in Vietnam. This paper describes health barriers experienced by women (and children by inference) in Vietnam, and measures how UHC, with reference to maternal health services and child mortality rates, is affected by selected social determinants of health (SDH), termed 'barriers'. Our study uses a cross-sectional design with data from the 2011 Vietnam Multiple Indicator Cluster Survey. The study sample includes 11,663 women, aged 15-49 years. Weighted frequency statistics are cross-tabulated with socioeconomic characteristics of the population to describe the extent and distribution of health barriers experienced by disadvantaged women and children in Vietnam. A subset of women who had a live birth in the preceding two years (n=1,383) was studied to assess the impact of barriers to UHC and health. Six multiple logistic regressions were run using three dependent variables in the previous two years: 1) antenatal care, 2) skilled birth attendants, and 3) child death in the previous 15 years. Independent predictor variables were: 1) low education (incomplete secondary education), 2) lack of access to one of four basic amenities. In a second set of regressions, a constructed composite barrier index replaced these variables. Odds ratios (ORs) and 95% confidence intervals (95% CI) were used to report regression results. In Vietnam, about 54% of women aged 15-49 years in 2011, had low education or lacked access to one of four basic amenities. About 38% of poor rural women from ethnic minorities experienced both barriers, compared with less than 1% of rich urban women from the ethnic majority. Incomplete secondary education or lack of one of four basic amenities was a factor significantly associated with lower access to skilled birth attendants (OR=0.28, 95% CI: 0.14-0.55; OR=0.19, 95% CI: 0.05-0.80) and a higher risk of having had a child death in the previous two years (OR=1.71, 95% CI: 1.28-2.30; OR=1.59, 95% CI: 1.20-2.10). Our study shows the need for accelerating education and infrastructure investments for ethnic minority communities living in rural areas so as to be able to contribute to equity-oriented progress toward UHC.

Piaget's Theory of Intellectual Development and Its Implication for Instructional Management at Pre-Secondary School Level

ERIC Educational Resources Information Center

Simatwa, Enose M. W.

2010-01-01

Instructional management focuses on planning, execution and evaluation of learning experiences. For teachers in pre-secondary schools to plan, execute and evaluate learning experiences effectively, they need to have good understanding of the process of cognitive development in children. Piaget has postulated that children progress through a series…

"Beyond" the Joys of Teaching: Stories from Four Novice Secondary Teachers

ERIC Educational Resources Information Center

Cooper, Jewell E.; He, Ye

2013-01-01

The purpose of this study was to document four novice secondary teachers' experiences as they progressed from the last year in their teacher education program through their first three years of teaching. Autobiographies, interviews, and focus groups were conducted to record their stories as novice teachers. In addition to the development of their…

Massachusetts English Language Learners' Profiles and Progress: A Report for the Massachusetts Department of Elementary and Secondary Education

ERIC Educational Resources Information Center

Slama, Rachel; Haynes, Erin; Sacks, Lynne; Lee, Dong Hoon; August, Diane

2015-01-01

The present study was commissioned by the Massachusetts Department of Elementary and Secondary Education (ESE) to provide a profile of Massachusetts English Language Learners (ELLs) and policy recommendations for improving their outcomes. ESE was concerned about previous study findings that most of these learners exited ELL instructional programs…

State Secondary CTE Standards: Developing a Framework out of a Patchwork of Policies

ERIC Educational Resources Information Center

Castellano, Marisa; Harrison, Linda; Schneider, Sherrie

2007-01-01

Many state educational administrators are currently working to define secondary career and technical education (CTE) content standards that specify the knowledge and skills students are expected to master in CTE program areas. The two-phase project on which this report is based explored (a) the progress and status of states in developing statewide…

Increasing Instructional Efficiency by Presenting Additional Stimuli in Learning Trials for Children with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Vladescu, Jason C.; Kodak, Tiffany M.

2013-01-01

The current study examined the effectiveness and efficiency of presenting secondary targets within learning trials for 4 children with an autism spectrum disorder. Specifically, we compared 4 instructional conditions using a progressive prompt delay. In 3 conditions, we presented secondary targets in the antecedent or consequence portion of…

Tracing Sustainability: An International Comparison of ESD Implementation into Lower Secondary Education

ERIC Educational Resources Information Center

Bagoly-Simó, Péter

2013-01-01

With the progress of the DESD, increasing numbers of researchers have been developing indicators to effectively measure the implementation of ESD in formal, informal and non-formal education. This paper aims to measure the implementation of ESD in secondary school curricula in three countries carrying the fingerprints of a developed (Germany),…

The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study.

PubMed

Křenek, Pavel; Benešová, Yvonne; Bienertová-Vašků, Julie; Vašků, Anna

2018-04-01

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, p a = 0.02; Taq, p g = 0.02, p a = 0.02; BsmI, p g = 0.02, p a = 0.04; ApaI, p g = 0.008, p a = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: p g = 0.01, p a = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT p corr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

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.

Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design.

PubMed

Chandramohan, Arun; Tulsian, Nikhil K; Anand, Ganesh S

2017-08-01

Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIα) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIα, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIα-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD.

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.

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.

PubMed

Spencer, Andrew; Prince, H Miles; Roberts, Andrew W; Prosser, Ian W; Bradstock, Kenneth F; Coyle, Luke; Gill, Devinder S; Horvath, Noemi; Reynolds, John; Kennedy, Nola

2009-04-10

Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival. Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability. After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio [HR], 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events. Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.

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.

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.

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.

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.

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.

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

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

PubMed

Haselkorn, Jodie K; Hughes, Christina; Rae-Grant, Alex; Henson, Lily Jung; Bever, Christopher T; Lo, Albert C; Brown, Theodore R; Kraft, George H; Getchius, Thomas; Gronseth, Gary; Armstrong, Melissa J; Narayanaswami, Pushpa

2015-11-24

To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). We systematically searched the literature (1970-2013) and classified articles using 2004 American Academy of Neurology criteria. This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0-6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0-8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2-6.5) (1 Class II). © 2015 American Academy of Neurology.

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

Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein

PubMed Central

Ardoin, Stacy P; Schanberg, Laura Eve; Sandborg, Christy I; Barnhart, Huiman X; Evans, Greg W; Yow, Eric; Mieszkalski, Kelly L; Ilowite, Norman T; Eberhard, Anne; Imundo, Lisa F; Kimura, Yuki; Levy, Deborah; von Scheven, Emily; Silverman, Earl; Bowyer, Suzanne L; Punaro, L; Singer, Nora G; Sherry, David D; McCurdy, Deborah K; Klein-Gitelman, Marissa; Wallace, Carol; Silver, Richard M; Wagner-Weiner, Linda; Higgins, Gloria C; Brunner, Hermine I; Jung, Lawrence; Soep, Jennifer B; Reed, Ann M; Thompson, Susan D

2014-01-01

Objective Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. Methods Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. Results Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. Conclusions Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. ClinicalTrials.gov identifier NCT00065806. PMID:23436914

Type 1 and type 2 cytokines in HIV infection -- a possible role in apoptosis and disease progression.

PubMed

Clerici, M; Fusi, M L; Ruzzante, S; Piconi, S; Biasin, M; Arienti, D; Trabattoni, D; Villa, M L

1997-06-01

The progression of HIV-infected subjects to AIDS was recently postulated to be controlled by the balance between type 1 cytokines (mainly enhancing cell-mediated immunity) and type 2 cytokines (mainly augmenting antibody production). Thus, progression of HIV infection was suggested to be accompanied by a decline of in vitro production of interleukin-2 (IL-2), IL-12 and interferon gamma (IFN-gamma) (type 1 cytokines) and an increase in the production of IL-4, IL-5, IL-6 and IL-10 (type 2 cytokines) by peripheral blood mononuclear cells of HIV-seropositive patients. According to this hypothesis, clinical markers of progression would be considered the loss of the ability to elicit a delayed-type hypersensitivity reaction to ubiquitous antigens (secondary to defective IL-2 production), hyper-IgE (secondary to increased IL-4 production) and hypereosynophilia (secondary to increased IL-5 production). The type 1 to type 2 shift was suggested to be predictive for the following events: (i) reduction in CD4 counts; (ii) time to AIDS diagnosis; (iii) time to death. Support for this hypothesis stems from the recent observation that a strong type 1/weak type 2 cytokine production profile was observed in HIV-seropositive patients with delayed or absent disease progression, whereas progression of HIV infection was characterized by a weak type 1/strong type 2 cytokine production profile. PBMC of HIV-seropositive individuals are susceptible to antigen-induced cell death (AICD) after antigen recognition via T-cell receptor (TcR). While TcR-induced AICD is seen in CD4+ and CD8+ cells programmed cell death induced by recall antigens is preferentially observed in CD4+ cells, a situation more closely resembling the CD4 depletion of HIV infection. Because type 1 cytokines reduce, whereas type 2 cytokines augment T-lymphocyte AICD, an increase in the concentration of type 2 cytokines could result in the decline in CD4+ cells seen in HIV infection.

[Molecular regulation of microbial secondary metabolites--a review].

PubMed

Wang, Linqi; Tan, Huarong

2009-04-01

Microbial secondary metabolites play an important role in the field of industry, agriculture, medicine and human health. The molecular regulation of secondary metabolites is gradually becoming noticeable and intriguing. In recent years, many researches have demonstrated that secondary metabolite biosynthesis is tightly linked to the physiological and developmental status in its producer. It is suggested that the biosynthesis of secondary metabolites involves in complex process concerning multi-level regulation. Here we reviewed the recent research progress on the molecular regulation of secondary metabolites in microorganisms. In known about ten thousand kinds of natural secondary metabolites, most of them (about 60%) were produced by Streptomycete. Therefore, the regulation of secondary metabolites in Streptomyces is chosen as the mainline in this review. Additionally, several well-studied antibiotics as the representative members were targeted. Finally, some suggestions, in response to the issues at present, have been presented in this paper.

Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis.

PubMed

Barro, Christian; Benkert, Pascal; Disanto, Giulio; Tsagkas, Charidimos; Amann, Michael; Naegelin, Yvonne; Leppert, David; Gobbi, Claudio; Granziera, Cristina; Yaldizli, Özgür; Michalak, Zuzanna; Wuerfel, Jens; Kappos, Ludwig; Parmar, Katrin; Kuhle, Jens

2018-05-30

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

Mitochondrial Bioenergetics and Dysfunction in Failing Heart.

PubMed

Sheeran, Freya L; Pepe, Salvatore

2017-01-01

Energy insufficiency has been recognized as a key feature of systolic heart failure. Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse. Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure. Diminished REDOX capacity with lower total glutathione and coenzyme Q 10 levels are also a feature of chronic left ventricular failure. Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications. In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins. Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure.

Multiple high voltage output DC-to-DC power converter

NASA Technical Reports Server (NTRS)

Cronin, Donald L. (Inventor); Farber, Bertrand F. (Inventor); Gehm, Hartmut K. (Inventor); Goldin, Daniel S. (Inventor)

1977-01-01

Disclosed is a multiple output DC-to-DC converter. The DC input power is filtered and passed through a chopper preregulator. The chopper output is then passed through a current source inverter controlled by a squarewave generator. The resultant AC is passed through the primary winding of a transformer, with high voltages induced in a plurality of secondary windings. The high voltage secondary outputs are each solid-state rectified for passage to individual output loads. Multiple feedback loops control the operation of the chopper preregulator, one being responsive to the current through the primary winding and another responsive to the DC voltage level at a selected output.

Functional analysis screening for multiple topographies of problem behavior.

PubMed

Bell, Marlesha C; Fahmie, Tara A

2018-04-23

The current study evaluated a screening procedure for multiple topographies of problem behavior in the context of an ongoing functional analysis. Experimenters analyzed the function of a topography of primary concern while collecting data on topographies of secondary concern. We used visual analysis to predict the function of secondary topographies and a subsequent functional analysis to test those predictions. Results showed that a general function was accurately predicted for five of six (83%) secondary topographies. A specific function was predicted and supported for a subset of these topographies. The experimenters discuss the implication of these results for clinicians who have limited time for functional assessment. © 2018 Society for the Experimental Analysis of Behavior.

Experimental and Computational Investigation of Multiple Injection Ports in a Convergent-Divergent Nozzle for Fluidic Thrust Vectoring

NASA Technical Reports Server (NTRS)

Waithe, Kenrick A.; Deere, Karen A.

2003-01-01

A computational and experimental study was conducted to investigate the effects of multiple injection ports in a two-dimensional, convergent-divergent nozzle, for fluidic thrust vectoring. The concept of multiple injection ports was conceived to enhance the thrust vectoring capability of a convergent-divergent nozzle over that of a single injection port without increasing the secondary mass flow rate requirements. The experimental study was conducted at static conditions in the Jet Exit Test Facility of the 16-Foot Transonic Tunnel Complex at NASA Langley Research Center. Internal nozzle performance was obtained at nozzle pressure ratios up to 10 with secondary nozzle pressure ratios up to 1 for five configurations. The computational study was conducted using the Reynolds Averaged Navier-Stokes computational fluid dynamics code PAB3D with two-equation turbulence closure and linear Reynolds stress modeling. Internal nozzle performance was predicted for nozzle pressure ratios up to 10 with a secondary nozzle pressure ratio of 0.7 for two configurations. Results from the experimental study indicate a benefit to multiple injection ports in a convergent-divergent nozzle. In general, increasing the number of injection ports from one to two increased the pitch thrust vectoring capability without any thrust performance penalties at nozzle pressure ratios less than 4 with high secondary pressure ratios. Results from the computational study are in excellent agreement with experimental results and validates PAB3D as a tool for predicting internal nozzle performance of a two dimensional, convergent-divergent nozzle with multiple injection ports.

Engine Tune-Up Service. Unit 4: Secondary Circuit. Posttests. Automotive Mechanics Curriculum.

ERIC Educational Resources Information Center

Morse, David T.

This book of posttests is designed to accompany the Engine Tune-Up Service Student Guide for Unit 4, Secondary Circuit, available separately as CE 031 214. Focus of the posttests is testing and servicing the secondary ignition circuit. One multiple choice posttest is provided that covers the seven performance objectives contained in the unit. (No…

Collaborative Leadership Practices among Ohio's Early College High School Principals and Their Post-Secondary Partners

ERIC Educational Resources Information Center

Carter, Allia L.

2012-01-01

This constructivist multiple-case study examined the collaborative leadership practices of seven secondary and seven post-secondary leaders who participate in Ohio's Early College High School Initiative (ECHSI). The 14 educational leaders in this study partnered in an effort to respond to the access and success of traditionally underrepresented…

Secondary Students' Quantification of Ratio and Rate: A Framework for Reasoning about Change in Covarying Quantities

ERIC Educational Resources Information Center

Johnson, Heather Lynn

2015-01-01

Contributing to a growing body of research addressing secondary students' quantitative and covariational reasoning, the multiple case study reported in this article investigated secondary students' quantification of ratio and rate. This article reports results from a study investigating students' quantification of rate and ratio as…

Finding the General Term for an Arithmetic Progression: Alternatives to the Formula

ERIC Educational Resources Information Center

Yeo, Joseph B. W.

2010-01-01

Secondary school students in Singapore are expected to find an expression for the general or "nth" term of an arithmetic progression (AP) without using the AP formula T[subscript n] = a + (n-1)d, where "a" is the first term, "n" is the number of terms and "d" is the common difference between successive…

Progressive Transitions in Chemistry Teachers' Understanding of Nature of Science Based on Historical Controversies

ERIC Educational Resources Information Center

Niaz, Mansoor

2009-01-01

The objective of this study is to facilitate progressive transitions in chemistry teachers understanding of nature of science in the context of historical controversies. Selected controversies referred to episodes that form part of the chemistry curriculum both at secondary and university freshman level. The study is based on 17 in-service…

English Language Proficiency and Content Assessment Performance: A Comparison of English Learners and Native English Speakers Achievement

ERIC Educational Resources Information Center

Miley, Suzi Keller; Farmer, Aarek

2017-01-01

As a result of the accountability requirements established in Title III of the Elementary and Secondary Educational Act (ESEA) legislation, English Learners (ELs) are expected to make progress in both content area academic achievement and English Language Proficiency (ELP). In Tennessee ELs progress is measured by administering WIDA-Access to…

Curriculum-Based Measurement in Science Learning: Vocabulary-Matching as an Indicator of Performance and Progress

ERIC Educational Resources Information Center

Espin, Christine A.; Busch, Todd W.; Lembke, Erica S.; Hampton, David D.; Seo, Kyounghee; Zukowski, Beth A.

2013-01-01

The technical adequacy of curriculum-based measures in the form of short and simple vocabulary-matching probes to predict students' performance and progress in science at the secondary level was investigated. Participants were 198 seventh-grade students from 10 science classrooms. Curriculum-based measurements (CBM) were 5-min vocabulary-matching…

Implementing Check in/Check out for Students with Intellectual Disability in Self-Contained Classrooms

ERIC Educational Resources Information Center

Boden, Lauren J.; Ennis, Robin P.; Jolivette, Kristine

2012-01-01

Check in/check out (CICO) is a secondary-tier intervention implemented within the framework of schoolwide positive behavior interventions and supports (SWPBIS) that uses school-based contingencies to encourage positive behavior. CICO is a five-step cycle which uses daily progress report cards (DPR) to monitor progress toward schoolwide or…

Aspirations, Progress and Perceptions of Boys from a Single Sex School Following the Changeover to Coeducation

ERIC Educational Resources Information Center

Yates, Shirley M.

2004-01-01

Career and further education aspirations, educational progress and perceptions of the learning environment were measured annually over three years in primary and secondary boys from a single sex non-government school, following the changeover to coeducation. Hierarchical Linear Modelling analyses revealed the significant role played by the career…

Evaluating Efforts to Enhance Health and Wellbeing in Scottish Secondary Schools

ERIC Educational Resources Information Center

Thorburn, Malcolm

2017-01-01

Curriculum for Excellence in Scotland outlines a policy vision of a more progressive, integrated and holistic form of education; a commitment which contains an obligation for health and well-being (HWB) to be a responsibility of all teachers. A critical policy analysis approach was utilized in order to review school-level progress in different…

An efficient method for the prediction of deleterious multiple-point mutations in the secondary structure of RNAs using suboptimal folding solutions

PubMed Central

Churkin, Alexander; Barash, Danny

2008-01-01

Background RNAmute is an interactive Java application which, given an RNA sequence, calculates the secondary structure of all single point mutations and organizes them into categories according to their similarity to the predicted structure of the wild type. The secondary structure predictions are performed using the Vienna RNA package. A more efficient implementation of RNAmute is needed, however, to extend from the case of single point mutations to the general case of multiple point mutations, which may often be desired for computational predictions alongside mutagenesis experiments. But analyzing multiple point mutations, a process that requires traversing all possible mutations, becomes highly expensive since the running time is O(nm) for a sequence of length n with m-point mutations. Using Vienna's RNAsubopt, we present a method that selects only those mutations, based on stability considerations, which are likely to be conformational rearranging. The approach is best examined using the dot plot representation for RNA secondary structure. Results Using RNAsubopt, the suboptimal solutions for a given wild-type sequence are calculated once. Then, specific mutations are selected that are most likely to cause a conformational rearrangement. For an RNA sequence of about 100 nts and 3-point mutations (n = 100, m = 3), for example, the proposed method reduces the running time from several hours or even days to several minutes, thus enabling the practical application of RNAmute to the analysis of multiple-point mutations. Conclusion A highly efficient addition to RNAmute that is as user friendly as the original application but that facilitates the practical analysis of multiple-point mutations is presented. Such an extension can now be exploited prior to site-directed mutagenesis experiments by virologists, for example, who investigate the change of function in an RNA virus via mutations that disrupt important motifs in its secondary structure. A complete explanation of the application, called MultiRNAmute, is available at [1]. PMID:18445289

Empirical Refinements of a Molecular Genetics Learning Progression: The Molecular Constructs

ERIC Educational Resources Information Center

Todd, Amber; Kenyon, Lisa

2016-01-01

This article describes revisions to four of the eight constructs of the Duncan molecular genetics learning progression [Duncan, Rogat, & Yarden, (2009)]. As learning progressions remain hypothetical models until validated by multiple rounds of empirical studies, these revisions are an important step toward validating the progression. Our…

Internal Shocks in the Magnetic Reconnection Jet in Solar Flares: Multiple Fast Shocks Created by the Secondary Tearing Instability

NASA Astrophysics Data System (ADS)

Tanuma, S.; Shibata, K.

2005-07-01

Space solar missions such as Yohkoh and RHESSI observe the hard X- and gamma-ray emission from energetic electrons in impulsive solar flares. Their energization mechanism, however, is unknown. In this Letter, we suggest that the internal shocks are created in the reconnection jet and that they are possible sites of particle acceleration. We examine how magnetic reconnection creates the multiple shocks by performing two-dimensional resistive magnetohydrodynamic simulations. In this Letter, we use a very small grid to resolve the diffusion region. As a result, we find that the current sheet becomes thin due to the tearing instability, and it collapses to a Sweet-Parker sheet. The thin sheet becomes unstable to the secondary tearing instability. Fast reconnection starts by the onset of anomalous resistivity immediately after the secondary tearing instability. During the bursty, time-dependent magnetic reconnection, the secondary tearing instability continues in the diffusion region where the anomalous resistivity is enhanced. As a result, many weak shocks are created in the reconnection jet. This situation produces turbulent reconnection. We suggest that multiple fast shocks are created in the jet and that the energetic electrons can be accelerated by these shocks.

The Study of Foreign Languages in England: Uptake in Secondary School and Progression to Higher Education

ERIC Educational Resources Information Center

Vidal Rodeiro, Carmen

2017-01-01

The decline in the numbers of students learning foreign languages in secondary schools in England, together with the low and decreasing number of top grades in these subjects, has raised concerns among educationalists, employers and politicians in the last few years. The aim of this research was, therefore, to investigate the uptake of and…

Gender and Headship in 2004: Reflections on Work in Progress

ERIC Educational Resources Information Center

Coleman, Marianne

2004-01-01

Most teachers in both secondary and primary schools are women, but most heads of secondary schools are men and the proportion of men who are heads in primary schools is large in comparison to the overall number of women in primary teaching. However, the proportion of women who are headteachers and deputy headteachers is growing. Although there are…

Middle-Level Secondary School Leaders: Potential, Constraints and Implications for Leadership Preparation and Development

ERIC Educational Resources Information Center

Gurr, David; Drysdale, Lawrie

2013-01-01

Purpose: The aim of this paper is to bring together for the first time three studies of middle-level leaders in secondary schools in Victoria, Australia. The studies span more than a decade and allow consideration of the progress in developing middle-level leadership roles. Design/methodology/approach: All studies followed a consistent approach…

A Case Study of Two Rural Secondary Schools in New Mexico: Perspectives on Leadership

ERIC Educational Resources Information Center

Iron Moccasin, Shawl D.

2012-01-01

The present study was designed to examine factors that led to the academic success of two rural secondary schools in New Mexico. The primary focus was on the characteristics and behaviors of leaders in two high-achieving rural schools and how these factors might have contributed to achievement of Adequate Yearly Progress (AYP) in school year…

Girls Getting to Secondary School Safely: Combating Gender-Based Violence in the Transportation Sector in Tanzania

ERIC Educational Resources Information Center

Mack, Laura

2009-01-01

While increasing girls' access to education is a global priority, there are numerous barriers that impede significant progress in achieving gender parity in schools. While enrollment of girl students is up in Tanzania, especially at the primary and secondary levels, AED has become concerned about the barriers girls face, including gender-based…

Inequality in the Transition from Primary to Secondary School: School Choices and Educational Disparities in Germany

ERIC Educational Resources Information Center

Pietsch, Marcus; Stubbe, Tobias C.

2007-01-01

This article explores the mechanisms of educational pathway decision making at the transition from primary to secondary school in the German education system by analysing data from the Progress in International Reading Literacy Study (PIRLS). The highly reliable data of the German sample of the 2001 PIRLS make it possible to take into…

Understanding and Implementing Section 2141(c) of the Elementary and Secondary Education Act. Policy-to-Practice Brief

ERIC Educational Resources Information Center

Potemski, Amy

2009-01-01

According to Section 2141(c) of the Elementary and Secondary Education Act (ESEA), as reauthorized by the No Child Left Behind Act (NCLB), local education agencies (LEAs) that fail to meet annual measurable objectives and make adequate yearly progress (AYP) for three consecutive years must enter into an agreement with the state education agency…

A Way Forward: A Progressive Vision for Reauthorizing the Elementary and Secondary Education Act

ERIC Educational Resources Information Center

Ayers, Jeremy; Brown, Cynthia

2011-01-01

Congress has the opportunity to move forward on education reform by reauthorizing the Elementary and Secondary Education Act, or ESEA, to ensure all children achieve their greatest potential. Unfortunately, it has yet to find the will to do so, to the detriment of American students and schools. ESEA is the largest and most significant federal…

An Analysis of Writing Activities in the Student Workbooks of a Secondary-Level Turkish Language Course

ERIC Educational Resources Information Center

Çerçi, Arif

2016-01-01

The purpose of this study is to analyze writing activities in the student workbooks of a secondary-level Turkish language course (grades 5 to 8) according to the principles of progressive writing. The study is descriptive and employs content analysis as a qualitative research paradigm. The writing activities of the books in this study all…

International Perspectives on the Nature of Mathematical Knowledge for Secondary Teaching: Progress and Dilemmas. Research Forum

ERIC Educational Resources Information Center

Doerr, Helen M.; Wood, Terry

2004-01-01

This research forum addresses the question: what is the nature of the mathematical knowledge that is needed for secondary teaching? Six international contributors: (1) Australia (Kaye Stacey); (2) Brazil (Marcelo Borba); (3) Israel (Ruhama Even); (4) Norway (Bodil Kleve and Barbara Jaworski); (5) Taiwan (Fou-Lai Lin); and (6) USA (Helen Doerr)…

Primary and Secondary Education in Morocco: From Access to School into Generalization to Dropout

ERIC Educational Resources Information Center

Mansouri, Zoulal; Moumine, Mohamed El Amine

2017-01-01

This article provides an overview of school wastage, namely repetition and dropout in primary and secondary schools in Morocco. It describes how this phenomenon has progressed since school was implemented in the 1960s. It shows that the fundamental principles of the education system established in the aftermath of Morocco?s independence in 1956…

Higher Education, the Universities and Secondary Teacher Training in Papua New Guinea

ERIC Educational Resources Information Center

Palmer, W. P.

1986-01-01

The purpose of this paper is to trace the growth of secondary and higher education in Papua New Guinea from its beginnings through the United Nations mission led by Sir Hugh Foot in 1962. The mission was most disappointed in the rate of educational progress in the territory of New Guinea which remained under United Nations mandate in the…

Dependence of the multiplicities of secondary particles on the impact parameter in collisions of high-energy neon and iron nuclei with photoemulsion nuclei

NASA Technical Reports Server (NTRS)

Dudkin, V. E.; Kovalev, E. E.; Nefedov, N. A.; Antonchik, V. A.; Bogdanov, S. D.; Kosmach, V. F.; Likhachev, A. YU.; Benton, E. V.; Crawford, H. J.

1995-01-01

A method is proposed for finding the dependence of mean multiplicities of secondaries on the nucleus-collision impact parameter from the data on the total interaction ensemble. The impact parameter has been shown to completely define the mean characteristics of an individual interaction event. A difference has been found between experimental results and the data calculated in terms of the cascade-evaporation model at impact-parameter values below 3 fm.

Multiplicities of secondaries in nuclear interactions, induced by 20Ne, 40Ar and 56Fe nuclei at 0.1-0.5 GeV/nucleon

NASA Technical Reports Server (NTRS)

Dudkin, V. E.; Kovalev, E. E.; Nefedov, N. A.; Antonchik, V. A.; Bogdanov, S. D.; Kosmach, V. F.; Hassan, J.; Benton, E. V.; Crawford, H. J.

1994-01-01

Multiplicities of various species of charged secondaries produced in inelastic interactions of 20Ne, 40Ar and 56Fe nuclei with emulsion nuclei at 0.1-0.5 GeV/nucleon have been measured. The data obtained are compared with the results for interactions of higher energy nuclei with emulsion nuclei. The dependences of the nucleus-nucleus interaction parameters on masses and energies of colliding nuclei are examined.

Sudden quadriplegia after acute cervical disc herniation.

PubMed

Sadanand, Venkatraman; Kelly, Michael; Varughese, George; Fourney, Daryl R

2005-08-01

Acute neurological deterioration secondary to cervical disc herniation not related to external trauma is very rare, with only six published reports to date. In most cases, acute symptoms were due to progression of disc herniation in the presence of pre-existing spinal canal stenosis. A 42-year-old man developed weakness and numbness in his arms and legs immediately following a sneeze. On physical examination he had upper motor neuron signs that progressed over a few hours to a complete C5 quadriplegia. An emergent magnetic resonance imaging study revealed a massive C4/5 disc herniation. He underwent emergency anterior cervical discectomy and fusion. Postoperatively, the patient remained quadriplegic. Eighteen days later, while receiving rehabilitation therapy, he expired secondary to a pulmonary embolus. Autopsy confirmed complete surgical decompression of the spinal cord. Our case demonstrates that acute quadriplegia secondary to cervical disc herniation may occur without a history of myelopathy or spinal canal stenosis after an event as benign as a sneeze.

Design Research on Mathematics Education: Investigating the Progress of Indonesian Fifth Grade Students' Learning on Multiplication of Fractions with Natural Numbers

ERIC Educational Resources Information Center

Shanty, Nenden Octavarulia; Hartono, Yusuf; Putri, Ratu Ilma Indra; de Haan, Dede

2011-01-01

This study aimed at investigating the progress of students' learning on multiplication fractions with natural numbers through the five activity levels based on Realistic Mathematics Education (RME) approach proposed by Streefland. Design research was chosen to achieve this research goal. In design research, the Hypothetical Learning Trajectory…

A comparative study of primary and secondary stereotypies.

PubMed

Ghosh, Debabrata; Rajan, Prashant V; Erenberg, Gerald

2013-12-01

This study compares primary stereotypies (repetitive, self-stimulating, and seemingly nonsensical movements that can occur within typically developing children) and secondary stereotypies (those occurring within autistic or mentally retarded children). Utilizing a retrospective chart review from 1995 to 2010, the current study compares primary and secondary stereotypies by the application of a classification system that organizes the movement by its type (motor only, phonic only, mixed) and complexity. In addition, it investigates other parameters associated with the movements such as duration, frequency, age, functional impairment, and progression. The sample group consisted of 28 primary and 28 secondary cases. Primary stereotypies were predominantly motor, simple, of shorter duration, and of less frequency, whereas secondary stereotypies had more vocalization, complexity, longer durations, and higher frequencies. Moreover, functional impairment due to stereotypies was noted in 3 primary and 7 secondary cases, and worsening of stereotypies was noted in 70% of primary versus 44% of secondary cases.

The effect of alcohol and red wine consumption on clinical and MRI outcomes in multiple sclerosis.

PubMed

Diaz-Cruz, Camilo; Chua, Alicia S; Malik, Muhammad Taimur; Kaplan, Tamara; Glanz, Bonnie I; Egorova, Svetlana; Guttmann, Charles R G; Bakshi, Rohit; Weiner, Howard L; Healy, Brian C; Chitnis, Tanuja

2017-10-01

Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS). To assess the association between alcohol and red wine consumption and MS course. MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol. 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, - 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, - 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1-3 glasses of red wine per week compared to nondrinkers. Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

High Levels of Peripheral Blood Circulating Plasma Cells as a Specific Risk Factor for Progression of Smoldering Multiple Myeloma

PubMed Central

Bianchi, Giada; Kyle, Robert A.; Larson, Dirk R.; Witzig, Thomas E.; Kumar, Shaji; Dispenzieri, Angela; Morice, William G.; Rajkumar, S. Vincent

2012-01-01

Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2–3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007 who had testing for circulating PCs using an immunofluorescent assay and adequate follow up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5000 ×106/L and/or > 5% cytoplasmic immunoglobulin (Ig) positive PCs per 100 peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 25%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 35%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2 to 3 years following diagnosis. PMID:22902364

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.

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants.

PubMed

Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J; Blum, Janice S; Sosenko, Jay M; Pugliese, Alberto; Geyer, Susan; Xu, Ping; Evans-Molina, Carmella

2016-06-01

The incidence of type 1 diabetes is increasing at a rate of 3-5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk. To test this in the TrialNet Pathway to Prevention (PTP) cohort, we analysed the influence of BMI, weight status and insulin resistance on progression from single to multiple islet autoantibodies (Aab) and progression from normoglycaemia to diabetes. HOMA1-IR was used to estimate insulin resistance in Aab-positive PTP participants. Cox proportional hazards models were used to evaluate the effects of BMI, BMI percentile (BMI%), weight status and HOMA1-IR on the progression of autoimmunity or the development of diabetes. Data from 1,310 single and 1,897 multiple Aab-positive PTP participants were included. We found no significant relationships between BMI, BMI%, weight status or HOMA1-IR and the progression from one to multiple Aabs. Similarly, among all Aab-positive participants, no significant relationships were found between BMI, weight status or HOMA1-IR and progression to diabetes. Diabetes risk was modestly increased with increasing BMI% among the entire cohort, in obese participants 13-20 years of age and with increasing HOMA1-IR in adult Aab-positive participants. Analysis of the accelerator hypothesis in the TrialNet PTP cohort does not suggest a broad influence of metabolic variables on diabetes risk. Efforts to identify other potentially modifiable environmental factors should continue.

All Students Are Not Equal: A Case Study of Geometry Teachers' Instructional Strategies When Trained in Multiple-Intelligence-Based Practices in Secondary Classrooms

ERIC Educational Resources Information Center

Davis, Cassandre Y.

2017-01-01

Over 50% of secondary students failed the geometry end-of-course test in a Florida school district, indicating a need to improve academic performance. Secondary school students' learning characteristics and the effectiveness of teachers' instructional strategies are imperative to educational success. In this qualitative case study, geometry…

Pre-Service Elementary School and Secondary Mathematics Teachers' Van Hiele Levels and Gender Differences

ERIC Educational Resources Information Center

Halat, Erdogan

2008-01-01

The aim of this study was to find and compare the pre-service elementary school and secondary mathematic teachers' reasoning stages in geometry. There were a total of 281 pre-service teachers, 125 elementary school teachers and 156 secondary mathematics teachers, involved in the study. The researcher employed a multiple-choice geometry test. This…

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

Progressive Damage Modeling of Notched Composites

NASA Technical Reports Server (NTRS)

Aitharaju, Venkat; Aashat, Satvir; Kia, Hamid; Satyanarayana, Arunkumar; Bogert, Philip

2016-01-01

There is an increased interest in using non-crimp fabric reinforced composites for primary and secondary structural weight savings in high performance automobile applications. However, one of the main challenges in implementing these composites is the lack of understanding of damage progression under a wide variety of loading conditions for general configurations. Towards that end, researchers at GM and NASA are developing new damage models to predict accurately the progressive failure of these composites. In this investigation, the developed progressive failure analysis model was applied to study damage progression in center-notched and open-hole tension specimens for various laminate schemes. The results of a detailed study with respect to the effect of element size on the analysis outcome are presented.

A review of urologic cancer patients with multiple primary malignancies.

PubMed

Mydlo, J H; Agins, J A; Donohoe, J; Grob, B M

2001-08-01

Much has been written on the treatment of solitary or multiple metastatic nodules that sometimes present in patients with urological malignancies. However, relatively little has been published regarding those patients with urological cancer who have another concomitant primary non-urologic tumor. We describe several cases of patients who presented with a urologic malignancy and a secondary non-urologic tumor. We also reviewed the literature using MEDLINE to gather information concerning this rare occurrence. We found that secondary malignancies, although not very common, are being increasingly reported. They are usually detected during the preoperative work-up of the primary tumor, usually by CT scan, ultrasound, or chest X-ray. Most authors suggest that treatment should be directed at the more aggressive lesion first, which would improve the overall status of the patient, and thus allow a better response from therapy for the secondary lesion. While patients with multiple primary malignancies are rare, the urologist should be alerted to this possibility when evaluating the patient for the initially presenting or detected tumor.

Development of In Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

DTIC Science & Technology

2014-02-01

multiple concussive traumatic brain injuries are at high risk for delayed, progressive neurological and psychiatric deterioration 1-9. This syndrome is...personnel 13, 14 and others who have sustained multiple concussive traumatic brain injuries 15-17 may also be at risk for this condition. Currently...11 Appendices……………………………………………………………………………... 12 4 INTRODUCTION: Athletes in contact sports who have sustained multiple concussive traumatic

Prevention of Graves' ophthalmopathy.

PubMed

Bartalena, Luigi

2012-06-01

Smoking is the most important risk factor for the occurrence/progression of Graves' ophthalmopathy (GO), as well as for its lower/slower response to immunosuppression. Accordingly, refrain from smoking should be urged, both as primary prevention (removal of risk factors in Graves' patients without GO), secondary prevention (early detection and treatment of asymptomatic/very mild GO) and tertiary prevention (reduction of complications/disability of overt GO). A 6-month course of 200 μg/day sodium selenite can prevent progression of mild GO to more severe GO and is, therefore, a form of secondary prevention and, probably, primary prevention. Correction of thyroid dysfunction and stable maintenance of euthyroidism are important preventive measures. The optimal treatment for hyperthyroidism in patients with GO is uncertain, because evidence demonstrating the superiority of antithyroid drugs over thyroid ablation (radioiodine, thyroidectomy, or both) is lacking. If radioiodine is used, low-dose steroid prophylaxis is recommended, particularly in smokers, to prevent radioiodine-associated GO progression. Copyright © 2011 Elsevier Ltd. All rights reserved.

Delayed-onset post-traumatic headache after a motor vehicle collision: a case report

PubMed Central

Stupar, Maja; Kim, Peter SY

2007-01-01

Introduction Headaches are common after a motor vehicle accident (MVA). Post-traumatic headaches share many clinical symptoms including the clinical course of primary headaches. Secondary headaches (including those resulting from a subdural hematoma) are not as common, but should be considered in cases of post-traumatic events particularly if clinical symptoms progress. Clinical Features A case of a patient with a post-traumatic subdural hematoma demonstrates the importance of carefully examining, properly diagnosing and managing patients that experience headaches after MVAs. This patient presented with uncomplicated low back pain, neck pain and headache which progressed at one month to include focal neurological deficits. Since clinical examination alone may not be sufficient to diagnose secondary headaches, immediate referral to the emergency department may be required. Conclusion Primary contact practitioners should be aware of the various causes of headaches that result after a MVA. Headaches, which do not respond or progress, should be followed aggressively to determine their source. PMID:17657301

[Localized scleroderma (morphea) in childhood].

PubMed

Weibel, L

2012-02-01

Localized scleroderma or morphea is a sclerosing connective tissue disease of the skin, which may affect underlying tissues such as subcutis, muscle and bone. Many patients show extracutaneous symptoms and antinuclear antibodies, however, secondary transformation into systemic sclerosis does not occur. Localized scleroderma usually begins in childhood with a wide variation in its clinical spectrum. The linear variant is the most common subtype in children, associated with a progressive course and increased risk of complications. The disease may progress over years and result in severe functional and cosmetic disability. The etiology of localized scleroderma remains unknown. A genetic background is suspected, while triggers such as trauma, vaccinations and infections may lead to secondary immunologic phenomena. Localized scleroderma often remains unrecognized for a long time, resulting in substantial delay in treatment. The combination of systemic corticosteroids and methotrexate has been established as first-line therapy for progressive (usually linear) disease, whereas phototherapy (UVA-1 or UVB-narrow band) is suitable for adolescents with superficial circumscribed subtypes.

Treating type 1 diabetes: from strategies for insulin delivery to dual hormonal control

PubMed Central

McCall, A. L.; Farhy, L. S.

2014-01-01

Type 1 diabetes is a disorder where slow destruction of pancreatic β-cells occurs through autoimmune mechanisms. The result is a progressive and ultimately complete lack of endogenous insulin. Due to β-cell lack, secondary abnormalities in glucagon and likely in incretins occur. These multiple hormonal abnormalities cause metabolic instability and extreme glycemic variability, which is the primary phenotype. As the disease progresses patients often develop hypoglycemia unawareness and defects in their counterregulatory defenses. Intensive insulin therapy may thus lead to 3-fold excess of severe hypoglycemia and severely hinder the effective and safe control of hyperglycemia. The main goal of the therapy for type 1 diabetes has long been physiological mimicry of normal insulin secretion based on monitoring which requires considerable effort and understanding of the underlying physiology. Attainment of this goal is challenged by the nature of the disease and our current lack of means to fully repair the abnormal endocrine pancreas interactive functions. As a result, various insulin preparations has been developed to partially compensate for the inability to deliver timely exogenous insulin directly to the portal/intrapancreatic circulation. It remains an ongoing task to identify the ideal routes and regimens of their delivery and potentially that of other hormones to restore the deficient and disordered hormonal environment of the pancreas to achieve a near normal metabolic state. Several recent technological advances help addressing these goals, including the rapid progress in insulin pumps, continuous glucose sensors, and ultimately the artificial pancreas closed-loop technology and the recent start of dual-hormone therapies. PMID:23732369

Chemotactic Cues for NOTCH1-Dependent Leukemia

PubMed Central

Piovan, Erich; Tosello, Valeria; Amadori, Alberto; Zanovello, Paola

2018-01-01

The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL. Leukemia patients often present with high-blood cell counts, diffuse disease with infiltration of the bone marrow, secondary lymphoid organs, and diffusion to the central nervous system (CNS). Chemokines are chemotactic cytokines that regulate migration of cells between tissues and the positioning and interactions of cells within tissue. Homeostatic chemokines and their receptors have been implicated in regulating organ-specific infiltration, but may also directly and indirectly modulate tumor growth. Recently, oncogenic NOTCH1 has been shown to regulate infiltration of leukemic cells into the CNS hijacking the CC-chemokine ligand 19/CC-chemokine receptor 7 chemokine axis. In addition, a crucial role for the homing receptor axis CXC-chemokine ligand 12/CXC-chemokine receptor 4 has been demonstrated in leukemia maintenance and progression. Moreover, the CCL25/CCR9 axis has been implicated in the homing of leukemic cells into the gut, particularly in the presence of phosphatase and tensin homolog tumor suppressor loss. In this review, we summarize the latest developments regarding the role of NOTCH signaling in regulating the chemotactic microenvironmental cues involved in the generation and progression of T-ALL and compare these findings to B-CLL. PMID:29666622

Multiple-port valve

DOEpatents

Doody, Thomas J.

1978-08-22

A multiple-port valve assembly is designed to direct flow from a primary conduit into any one of a plurality of secondary conduits as well as to direct a reverse flow. The valve includes two mating hemispherical sockets that rotatably receive a spherical valve plug. The valve plug is attached to the primary conduit and includes diverging passageways from that conduit to a plurality of ports. Each of the ports is alignable wih one or more of a plurality of secondary conduits fitted into one of the hemispherical sockets. The other hemispherical socket includes a slot for the primary conduit such that the conduit's motion along that slot with rotation of the spherical plug about various axes will position the valve-plug ports in respect to the secondary conduits.

The Failure of Progressive Classroom Reform: Lessons from the Curriculum Reform Implementation Project in Papua New Guinea

ERIC Educational Resources Information Center

Guthrie, Gerard

2012-01-01

Progressive education has been an article of educational faith in Papua New Guinea during the last 50 years but the best available evidence indicates that major reforms to formalistic curriculum and teaching in primary and secondary classrooms have failed during this period despite large-scale professional, administrative and financial support. In…

Proceedings of the New England Conference on Ocean Science Education, Woods Hole, Massachusetts, May 1966.

ERIC Educational Resources Information Center

Mangelsdorf, Frederick E.; And Others

Reported are the papers presented at the New England Conference on Ocean Science Education. The purpose of the conference was to bring together prominent oceanographers and New England educators at the primary and secondary level to discuss current progress in oceanographic research and to relate this progress to the needs of schools for materials…

Middle Attainers and 14-19 Progression in England: Half-Served by New Labour and Now Overlooked by the Coalition?

ERIC Educational Resources Information Center

Hodgson, Ann; Spours, Ken

2014-01-01

In the context of the international problem of "early school leaving", this paper explores the issue of sustained participation in upper secondary education in England. It focuses in particular on the position of middle attainers, who constitute a large proportion of the cohort and whose progress will be vital in realising the…

Promoting the Social Inclusion and Academic Progress of Gypsy, Roma and Traveller Children: A Secondary School Case Study

ERIC Educational Resources Information Center

Gould, Siobhan

2017-01-01

The aim of this study was to identify support strategies used to promote "social inclusion" and "academic progress" of Key Stage 3 and 4 Gypsy, Roma and Traveller (GRT) pupils. The study used an interpretivist approach, incorporating an embedded single case study with several participant groups, namely GRT pupils, GRT parents,…

Leadership Progression of Muslim Male Teachers: Interplay of Ethnicity, Faith and Visibility

ERIC Educational Resources Information Center

Shah, Saeeda; Shaikh, Jalil

2010-01-01

The paper focuses on perceived barriers to the career progression of Muslim male teachers to leadership positions in English secondary schools, exploring the impact of ethnicity, faith and Muslim visibility in the post 9/11 scenario. It draws on a small study of Muslim male teachers (MMTs) from five boroughs in London to explore their experiences…

Formative Information Using Student Growth Percentiles for the Quantification of English Language Learners' Progress in Language Acquisition

ERIC Educational Resources Information Center

Taherbhai, Husein; Seo, Daeryong; O'Malley, Kimberly

2014-01-01

English language learners (ELLs) are the fastest growing subgroup in American schools. These students, by a provision in the reauthorization of the Elementary and Secondary Education Act, are to be supported in their quest for language proficiency through the creation of systems that more effectively measure ELLs' progress across years. In…

Vegetable and fruit intake after diagnosis and risk of prostate cancer progression.

PubMed

Richman, Erin L; Carroll, Peter R; Chan, June M

2012-07-01

Cruciferous vegetables, tomato sauce and legumes have been associated with reduced risk of incident advanced prostate cancer. In vitro and animal studies suggest these foods may inhibit progression of prostate cancer, but there are limited data in men. Therefore, we prospectively examined whether intake of total vegetables, and specifically cruciferous vegetables, tomato sauce and legumes, after diagnosis reduce risk of prostate cancer progression among 1,560 men diagnosed with non-metastatic prostate cancer and participating in the Cancer of the Prostate Strategic Urologic Research Endeavor, a United States prostate cancer registry. As a secondary analysis, we also examined other vegetable subgroups, total fruit and subgroups of fruits. The participants were diagnosed primarily at community-based clinics and followed from 2004 to 2009. We assessed vegetable and fruit intake via a semi-quantitative food frequency questionnaire, and ascertained prostate cancer outcomes via urologist report and medical records. We observed 134 events of progression (53 biochemical recurrences, 71 secondary treatments likely due to recurrence, 6 bone metastases and 4 prostate cancer deaths) during 3,171 person-years. Men in the fourth quartile of post-diagnostic cruciferous vegetable intake had a statistically significant 59% decreased risk of prostate cancer progression compared to men in the lowest quartile (hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.22, 0.76; p-trend: 0.003). No other vegetable or fruit group was statistically significantly associated with risk of prostate cancer progression. In conclusion, cruciferous vegetable intake after diagnosis may reduce risk of prostate cancer progression. Copyright © 2011 UICC.

Early versus Deferred Treatment for Smoldering Multiple Myeloma: A Meta-Analysis of Randomized, Controlled Trials

PubMed Central

Tompkins, Van S.; Gao, Lu; Wu, Xiaosong; Tao, Yi; Hu, Xiaojing; Hou, Jun; Han, Ying; Xu, Hongwei; Zhan, Fenghuang; Shi, Jumei

2014-01-01

Purpose Whether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM. Methods MEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events. Results Overall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59). Conclusions Early treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn’t significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence. PMID:25279718

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.

A New Classification for Pathologies of Spinal Meninges-Part 2: Primary and Secondary Intradural Arachnoid Cysts.

PubMed

Klekamp, Jörg

2017-08-01

Spinal intradural arachnoid cysts are rare causes of radiculopathy or myelopathy. Treatment options include resection, fenestration, or cyst drainage. To classify intradural spinal arachnoid cysts and present results of their treatment. Among 1519 patients with spinal space occupying lesions, 130 patients demonstrated intradural arachnoid cysts. Neuroradiological and surgical features were reviewed and clinical data analyzed. Twenty-one patients presented arachnoid cysts as a result of an inflammatory leptomeningeal reaction related to meningitis, subarachnoid hemorrhage, intrathecal injections, intradural surgery, or trauma, ie, secondary cysts. For the remaining 109 patients, no such history could be elucidated, ie, primary cysts. Forty-six percent of primary and 86% of secondary cysts were associated with syringomyelia. Patients presented after an average history of 53 ± 88 months. There were 122 thoracic and 7 lumbar cysts plus 1 cervical cyst. Fifty-nine patients with primary and 15 patients with secondary cysts underwent laminotomies with complete or partial cyst resection and duraplasty. Mean follow-up was 57 ± 52 months. In the first postoperative year, profound improvements for primary cysts were noted, in contrast to marginal changes for secondary cysts. Progression-free survival for 10 years following surgery was determined as 83% for primary compared to 15% for secondary cysts. Despite differences in clinical presentation, progression-free survival was almost identical for patients with or without syringomyelia. Complete or partial resection leads to favorable short- and long-term results for primary arachnoid cysts. For secondary cysts, surgery can only provide clinical stabilization for a limited time due to the often extensive arachnoiditis. Copyright © 2017 by the Congress of Neurological Surgeons

78 FR 23335 - Energy Conservation Program: Energy Conservation Standards for Distribution Transformers

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-18

... Basic Impulse Level 4. Dual/Multiple-Voltage Primary Windings 5. Dual/Multiple-Voltage Secondary Windings 6. Loading B. Technological Feasibility 1. General 2. Maximum Technologically Feasible Levels C...

Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.

PubMed

Chaudhry, Burhan Z; Cohen, Jeffrey A; Conway, Devon S

2017-10-01

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

Reversible posterior leukoencephalopathy syndrome secondary to systemic-onset juvenile idiopathic arthritis: A case report and review of the literature.

PubMed

Zhang, Pingping; Li, Xiaofeng; Li, Yating; Wang, Jing; Zeng, Huasong; Zeng, Xiaofeng

2015-01-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical syndrome based on changes in clinical imaging, and it has been reported to mainly occur in adults. However, it has been recently discovered that RPLS is also prevalent in infant patients, particularly in those using glucocorticoids, immunosuppressant medications and cytotoxic drugs. The current study presents a 5-year-old male with a previous diagnosis of systemic-onset juvenile idiopathic arthritis (SoJIA) and macrophage-activation syndrome who developed posterior reversible encephalopathy syndrome during treatment with glucocorticoids, disease-modifying antirheumatic drugs and biological agent (etanercept) therapy. After ~5 days of treatment, the patient made a complete clinical recovery; the magnetic resonance imaging reviewed 2 weeks later showed that the previous hyper-intensity signal had disappeared and the multiple lesions in the brain had been completely absorbed. The case report shows that, conforming to recent literature, SoJIA in infants should be considered a risk factor for developing RPLS. The clinical manifestations of the disease are multiple, but usually reversible, and the patients mostly have a good prognosis. Rapid diagnosis and treatment is essential as early treatment may prevent progression to irreversible brain damage. By increasing the awareness of RPLS, the patient care may improve and further insight may be gained.

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.

Refractory Pain Management in Amyloid-Associated Peripheral Neuropathy.

PubMed

Warner, Nafisseh S; Watson, James C; Bendel, Markus A; Moeschler, Susan M

2018-05-01

Systemic amyloidosis is a disease that often involves multiple organ systems, including the peripheral nervous system. Patients may present with severe, refractory neuropathic pain; however, the optimal treatment approach for pain for these patients remains unclear. A man with severe, refractory neuropathic pain in his bilateral upper and lower extremities and the trunk secondary to amyloid neuropathy is presented. Multiple medication trials, including neuropathic and opioid agents, produced considerable adverse effects and minimal relief. Scrambler therapy, a novel electrical stimulation modality, was used and was associated with substantial short-term but nonsustained benefit. Spinal cord stimulation was considered, but given his diffuse symptoms, it was deemed a less-than-optimal approach. Ultimately, an intrathecal drug delivery system was placed with infusion of hydromorphone, resulting in substantial pain reduction in all involved areas and with an improved adverse effect profile. This intervention resulted in immense improvement in the patient's quality of life, despite progression of his systemic amyloidosis. Severe pain in the setting of amyloid neuropathy is often difficult to treat. To our knowledge, this represents the first report of Scrambler therapy or an implanted intrathecal drug delivery system used for a patient with refractory amyloidosis-related neuropathic pain, resulting in substantial analgesic benefit and improved quality of life.

Relationship of Non-Verbal Intelligence Materials as Catalyst for Academic Achievement and Peaceful Co-Existence among Secondary School Students in Nigeria

ERIC Educational Resources Information Center

Sambo, Aminu

2015-01-01

This paper examines students' performance in Non-verbal Intelligence tests relative academic achievement of some selected secondary school students. Two hypotheses were formulated with a view to generating data for the ease of analyses. Two non-verbal intelligent tests viz: Raven's Standard Progressive Matrices (SPM) and AH[subscript 4] Part II…

A Smooth Trajectory: Developing Continuity and Progression between Primary and Secondary Science Education through a Jointly-Planned Projectiles Project

ERIC Educational Resources Information Center

Davies, Dan; McMahon, Kendra

2004-01-01

This article reports on findings from a two-year project--'Improving Science Together'--undertaken in 20 primary and four secondary schools in and around Bristol, UK. The project was funded by the pharmaceutical company AstraZeneca PLC as part of their national Science Teaching Trust initiative, and had as one of its aims the development of…

A Review of Progress: Model Secondary School for the Deaf; The First Five Years (1970-1975). Report.

ERIC Educational Resources Information Center

Model Secondary School for the Deaf, Washington, DC.

Presented is the report of a review panel made up of educators, deaf persons, and parents of deaf children on the first five years of the Model Secondary School for the Deaf operated by Gallaudet College. Sections of the report include observations and recommendations in the following areas: the school's mission; the concept of model; the…

Sustaining Change: The Struggle to Maintain Identity at Central Park East Secondary School

ERIC Educational Resources Information Center

Suiter, Diane

2009-01-01

Central Park East Secondary School (CPESS) in East Harlem was one of the most highly acclaimed and successful schools to come out of the period of school reform in the 1980s from which the Coalition of Essential Schools emerged. Noted progressive educator Deborah Meier founded CPESS in 1985 not as a reform model, but as a continuation of the…

Serving Students, Science, or Society? The Secondary School Physics Curriculum in the United States, 1930-65.

ERIC Educational Resources Information Center

Donahue, David M.

1993-01-01

Reviews the reform of secondary school physics in the United States from the 1930s through the mid-1960s. Describes the impact of progressive education, World War II, and the post-Sputnik reforms. Points out differences between past reform efforts and the current Project 2061 of the American Association for the Advancement of Science (AAAS). (CFR)

Conceptualizing RTI in 21st-Century Secondary Science Classrooms: Video Games' Potential to Provide Tiered Support and Progress Monitoring for Students with Learning Disabilities

ERIC Educational Resources Information Center

Marino, Matthew T.; Beecher, Constance C.

2010-01-01

Secondary schools across the United States are adopting response to intervention (RTI) as a means to identify students with learning disabilities (LD) and provide tiered instructional interventions that benefit all students. The majority of current RTI research focuses on students with reading difficulties in elementary school classrooms.…

Is the Coach Ready for the Game? A Self-Study of Literacy Coaching in a Secondary School

ERIC Educational Resources Information Center

Perry, Barbara J.

2010-01-01

Content area teachers at the secondary level often complain that the students are unwilling or unable to read and comprehend the textbooks. Yet these teachers have seldom had instruction in the teaching of reading. They state that teaching of reading is someone else's job. They state that they need to progress through the entire textbook, and that…

Growing Musicians in English Secondary Schools at Key Stage 3 (Age 11-14)

ERIC Educational Resources Information Center

Dalladay, Christopher

2017-01-01

The National Curriculum for Music in England at Key Stage 3 (KS3; age 11-14) declares its purpose that pupils should be inspired to "develop a love of music and their talent as musicians" (DfE, 2013: KS3 Music). The Office for Standards in Education (Ofsted) have criticised secondary schools for a lack of progress in the musical…

Assessment for Qualification and Certification in Upper Secondary Education: A Review of Country Practices and Research Evidence. OECD Education Working Papers, No. 83

ERIC Educational Resources Information Center

Dufaux, Stefanie

2012-01-01

Within the policy field of student assessment, the assessment of students for qualification and certification in upper secondary education has special importance since key decisions for the progression of students may be taken on the basis of assessment results. Students in most OECD countries face increased specialisation in upper secondary…

Sex Differences in Self-Estimation of Multiple Intelligences among Portuguese Adolescents

ERIC Educational Resources Information Center

Neto, Felix; Ruiz, Fatima; Furnham, Adrian

2008-01-01

This study investigated the relationship among sex, attitude toward intelligence, and self-estimation of multiple intelligences for self and parents among Portuguese adolescents in secondary schools. Two hundred and forty-two adolescents estimated their own and their parents' IQ scores on each of Gardner's 10 multiple intelligences: verbal…

The Correlation of Multiple Intelligences for the Achievements of Secondary Students

ERIC Educational Resources Information Center

Ahvan, Yaghoob Raissi; Pour, Hossein Zainali

2016-01-01

The present study attempts to investigate the relationship between the multiple intelligences and the academic performance achievement levels of high school students based on Gardner's multiple intelligences theory. This was a descriptive correlation study. To accomplish this purpose, 270 students of high school of Bandar Abbas selected by…

Working memory and fluid intelligence: capacity, attention control, and secondary memory retrieval.

PubMed

Unsworth, Nash; Fukuda, Keisuke; Awh, Edward; Vogel, Edward K

2014-06-01

Several theories have been put forth to explain the relation between working memory (WM) and gF. Unfortunately, no single factor has been shown to fully account for the relation between these two important constructs. In the current study we tested whether multiple factors (capacity, attention control, and secondary memory) would collectively account for the relation. A large number of participants performed multiple measures of each construct and latent variable analyses were used to examine the data. The results demonstrated that capacity, attention control, and secondary memory were uniquely related to WM storage, WM processing, and gF. Importantly, the three factors completely accounted for the relation between WM (both processing and storage) and gF. Thus, although storage and processing make independent contributions to gF, both of these contributions are accounted for by variation in capacity, attention control and secondary memory. These results are consistent with the multifaceted view of WM, suggesting that individual differences in capacity, attention control, and secondary memory jointly account for individual differences in WM and its relation with gF. Copyright © 2014 Elsevier Inc. All rights reserved.

Working Memory and Fluid Intelligence: Capacity, Attention Control, and Secondary Memory Retrieval

PubMed Central

Unsworth, Nash; Fukuda, Keisuke; Awh, Edward; Vogel, Edward K.

2015-01-01

Several theories have been put forth to explain the relation between working memory (WM) and gF. Unfortunately, no single factor has been shown to fully account for the relation between these two important constructs. In the current study we tested whether multiple factors (capacity, attention control, and secondary memory) would collectively account for the relation. A large number of participants performed multiple measures of each construct and latent variable analyses were used to examine the data. The results demonstrated that capacity, attention control, and secondary memory were uniquely related to WM storage, WM processing, and gF. Importantly, the three factors completely accounted for the relation between WM (both processing and storage) and gF. Thus, although storage and processing make independent contributions to gF, both of these contributions are accounted for by variation in capacity, attention control and secondary memory. These results are consistent with the multifaceted view of WM, suggesting that individual differences in capacity, attention control, and secondary memory jointly account for individual differences in WM and its relation with gF. PMID:24531497

Should Secondary Schools Buy Local Area Networks?

ERIC Educational Resources Information Center

Hyde, Hartley

1986-01-01

The advantages of microcomputer networks include resource sharing, multiple user communications, and integrating data processing and office automation. This article nonetheless favors stand-alone computers for Australian secondary school classrooms because of unreliable hardware, software design, and copyright problems, and individual progress…

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

A combined inspiratory and expiratory muscle training program improves respiratory muscle strength and fatigue in multiple sclerosis.

PubMed

Ray, Andrew D; Udhoji, Supriya; Mashtare, Terry L; Fisher, Nadine M

2013-10-01

To determine the effects of a short-duration, combined (inspiratory and expiratory), progressive resistance respiratory muscle training (RMT) protocol on respiratory muscle strength, fatigue, health-related quality of life, and functional performance in individuals with mild-to-moderate multiple sclerosis (MS). Quasi-experimental before-after trial. University rehabilitation research laboratory. Volunteers with MS (N=21) were divided into 2 groups: RMT (n=11; 9 women, 2 men; mean age ± SD, 50.9 ± 5.7y, mean Expanded Disability Status Scale score ± SD, 3.2 ± 1.9) and a control group that did not train (n=10; 7 women, 3 men; mean age ± SD, 56.2 ± 8.8y, mean Expanded Disability Status Scale score ± SD, 4.4 ± 2.1). Expanded Disability Status Scale scores ranged from 1 to ≤6.5. No patients withdrew from the study. Training was a 5-week combined progressive resistance RMT program, 3d/wk, 30 minutes per session. The primary outcome measures were maximal inspiratory pressure and expiratory pressure and the Modified Fatigue Impact Scale. All subjects completed secondary measures of pulmonary function, the six-minute walk test, the timed stair climb, the Multiple Sclerosis Self-Efficacy Scale, the Medical Outcomes Study 36-Item Short-Form Health Survey, and the Physical Activity Disability Scale. Maximal inspiratory pressure and expiratory pressure (mean ± SD) increased 35% ± 22% (P<.001) and 26% ± 17% (P<.001), respectively, whereas no changes were noted in the control group (12% ± 23% and -4% ± 17%, respectively). RMT improved fatigue (Modified Fatigue Impact Scale, P<.029), with no change or worsening in the control group. No changes were noted in the six-minute walk test, stair climb, Multiple Sclerosis Self-Efficacy Scale, or Physical Activity Disability Scale in the RMT group. The control group had decreases in emotional well-being and general health (Medical Outcomes Study 36-Item Short-Form Health Survey). A short-duration, combined RMT program improved inspiratory and expiratory muscle strength and reduced fatigue in patients with mild to moderate MS. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Progressive exercise preconditioning protects against circulatory shock during experimental heatstroke.

PubMed

Hung, Ching-Hsia; Chang, Nen-Chung; Cheng, Bor-Chih; Lin, Mao-Tsun

2005-05-01

Heat shock protein (HSP) 72 expression protects against arterial hypotension in rat heatstroke. HSP72 can also be induced in multiple organs, including hearts from rats with endurance exercise. We validated the hypothesis that progressive exercise preconditioning may confer cardiovascular protection during heatstroke by inducing the overexpression of HSP72 in multiple organs. To deal with the matter, we assessed the effects of heatstroke on mean arterial pressure, heart rate, cardiac output, stroke volume, total peripheral vascular resistance, colonic temperature, blood gases, and serum or tissue levels of tumor necrosis factor-alpha (TNF-alpha) in urethane-anesthetized rats pretreated without or with progressive exercise training for 1, 2, or 3 weeks. In addition, HSP72 expression in multiple organs was determined in different groups of animals. Heatstroke was induced by exposing the rats to a high blanket temperature (43 degrees C); the moment at which mean arterial pressure decreased from the peak value was taken as the time of heatstroke onset. Previous exercise training for 3 weeks, but not 1 or 2 weeks, conferred significant protection against hyperthermia, arterial hypotension, decreased cardiac output, decreased stroke volume, decreased peripheral vascular resistance, and increased levels of serum or tissue TNF-alpha during heatstroke and correlated with overexpression of HSP72 in multiple organs, including heart, liver, and adrenal gland. However, 10 days after 3 weeks of progressive exercise training, when HSP72 expression in multiple organs returned to basal values, the beneficial effects exerted by 3 weeks of exercise training were no longer observed. These results strongly suggest that HSP72 preconditioning with progressive exercise training protects against hyperthermia, circulatory shock, and TNF-alpha overproduction during heatstroke.

Increasing instructional efficiency by presenting additional stimuli in learning trials for children with autism spectrum disorders.

PubMed

Vladescu, Jason C; Kodak, Tiffany M

2013-12-01

The current study examined the effectiveness and efficiency of presenting secondary targets within learning trials for 4 children with an autism spectrum disorder. Specifically, we compared 4 instructional conditions using a progressive prompt delay. In 3 conditions, we presented secondary targets in the antecedent or consequence portion of learning trials, or in the absence of prompts and reinforcement. In the fourth condition (control), we did not include secondary targets in learning trials. Results replicate and extend previous research by demonstrating that the majority of participants acquired secondary targets presented in the antecedent and consequent events of learning trials. © Society for the Experimental Analysis of Behavior.

Lessons from the atomic bomb about secondary MDS.

PubMed

Hata, Tomoko; Imanishi, Daisuke; Miyazaki, Yasushi

2014-12-01

Myelodysplastic syndromes (MDSs) is a hematological neoplasm defined by ineffective hematopoiesis, dysplasia of hematopoietic cells, and risk of progression to acute leukemia. MDS occurs as de novo or secondary, and chemoradiotherapy for cancers is thought to increase the risk of MDS among patients. Recently, an epidemiological study for MDS among A-bomb survivors was performed, and it clearly demonstrated that the exposure to external radiation significantly increased the risk of MDS. Precise epidemiological data among survivors have revealed important clinical factors related to the risk of leukemias. In this review, by comparing data for secondary MDS and leukemia/MDS among survivors, several factors which would affect the risk of MDS, especially secondary MDS, are discussed.

Acute severe hemorrhage secondary to arterial invasion in a dog with thyroid carcinoma.

PubMed

Slensky, Kimberly A; Volk, Susan W; Schwarz, Tobias; Duda, Lili; Mauldin, Elizabeth A; Silverstein, Deborah

2003-09-01

A 7-year-old spayed female Labrador Retriever was referred because of progressive swelling and bruising of the neck, hemothorax, a possible mediastinal mass, and stridor. At the time of admission, the dog was recumbent, mentally dull, tachycardic, and hypothermic. Fluid therapy with hydroxyethyl starch and a balanced electrolyte solution was administered because of presumed hypovolemic shock secondary to hemorrhage; multiple units of packed RBCs and fresh frozen plasma were also administered. On the basis of the computed tomographic images, extensive subcutaneous, subfascial, and cranial mediastinal hemorrhage; hemothorax; prescapular lymphadenopathy; and a contrast-enhancing mass in the left cranioventral aspect of the neck were diagnosed. Exploratory surgery of the neck was performed. All subcutaneous structures were encased in a large blood clot. During dissection of the clot, pulsatile bleeding was observed just caudal to and to the left of the larynx; ligation of the left common carotid artery resulted in immediate cessation of the pulsatile bleeding. Further surgical exploration revealed a 2.5 x 2.5-cm mass adhered to the left common carotid artery at the level of the branching to the left cranial thyroid artery. The mass was removed; the histologic diagnosis was thyroid carcinoma. Three weeks after surgery, treatment with a combination of radiation and chemotherapy (doxorubicin and carboplatin) was begun. Thirteen months after surgery, the dog continued to be free from clinical signs of disease.

Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing.

PubMed

Weber, Stefanie; Büscher, Anja K; Hagmann, Henning; Liebau, Max C; Heberle, Christian; Ludwig, Michael; Rath, Sabine; Alberer, Martin; Beissert, Antje; Zenker, Martin; Hoyer, Peter F; Konrad, Martin; Klein, Hanns-Georg; Hoefele, Julia

2016-01-01

Steroid-resistant nephrotic syndrome (SRNS) is a severe cause of progressive renal disease. Genetic forms of SRNS can present with autosomal recessive or autosomal dominant inheritance. Recent studies have identified mutations in multiple podocyte genes responsible for SRNS. Improved sequencing methods (next-generation sequencing, NGS) now promise rapid mutational testing of SRNS genes. In the present study, a simultaneous screening of ten SRNS genes in 37 SRNS patients was performed by NGS. In 38 % of the patients, causative mutations in one SRNS gene were found. In 22 % of the patients, in addition to these mutations, a secondary variant in a different gene was identified. This high incidence of accumulating sequence variants was unexpected but, although they might have modifier effects, the pathogenic potential of these additional sequence variants seems unclear so far. The example of molecular diagnostics by NGS in SRNS patients shows that these new sequencing technologies might provide further insight into molecular pathogenicity in genetic disorders but will also generate results, which will be difficult to interpret and complicate genetic counseling. Although NGS promises more frequent identification of disease-causing mutations, the identification of causative mutations, the interpretation of incidental findings and possible pitfalls might pose problems, which hopefully will decrease by further experience and elucidation of molecular interactions.

Detection of circulating breast cancer cells using photoacoustic flow cytometry

NASA Astrophysics Data System (ADS)

Bhattacharyya, Kiran

According to the American Cancer Society, more than 200,000 new cases of breast cancer are expected to be diagnosed this year. Moreover, about 40,000 women died from breast cancer last year alone. As breast cancer progresses in an individual, it can transform from a localized state to a metastatic one with multiple tumors distributed through the body, not necessarily contained within the breast. Metastasis is the spread of cancer through the body by circulating tumor cells (CTCs) which can be found in the blood and lymph of the diagnosed patient. Diagnosis of a metastatic state by the discovery of a secondary tumor can often come too late and hence, significantly reduce the patient's chance of survival. There is a current need for a CTC detection method which would diagnose metastasis before the secondary tumor occurs or reaches a size resolvable by current imaging systems. Since earlier detection would improve prognosis, this study proposes a method of labeling of breast cancer cells for detection with a photoacoustic flow cytometry system as a model for CTC detection in human blood. Gold nanoparticles and fluorescent polystyrene nanoparticles are proposed as contrast agents for T47D, the breast cancer cell line of choice. The labeling, photoacoustic detection limit, and sensitivity are first characterized and then applied to a study to show detection from human blood.

RNA 3D Modules in Genome-Wide Predictions of RNA 2D Structure

PubMed Central

Theis, Corinna; Zirbel, Craig L.; zu Siederdissen, Christian Höner; Anthon, Christian; Hofacker, Ivo L.; Nielsen, Henrik; Gorodkin, Jan

2015-01-01

Recent experimental and computational progress has revealed a large potential for RNA structure in the genome. This has been driven by computational strategies that exploit multiple genomes of related organisms to identify common sequences and secondary structures. However, these computational approaches have two main challenges: they are computationally expensive and they have a relatively high false discovery rate (FDR). Simultaneously, RNA 3D structure analysis has revealed modules composed of non-canonical base pairs which occur in non-homologous positions, apparently by independent evolution. These modules can, for example, occur inside structural elements which in RNA 2D predictions appear as internal loops. Hence one question is if the use of such RNA 3D information can improve the prediction accuracy of RNA secondary structure at a genome-wide level. Here, we use RNAz in combination with 3D module prediction tools and apply them on a 13-way vertebrate sequence-based alignment. We find that RNA 3D modules predicted by metaRNAmodules and JAR3D are significantly enriched in the screened windows compared to their shuffled counterparts. The initially estimated FDR of 47.0% is lowered to below 25% when certain 3D module predictions are present in the window of the 2D prediction. We discuss the implications and prospects for further development of computational strategies for detection of RNA 2D structure in genomic sequence. PMID:26509713

Curriculum-Based Measurement of Oral Reading: Quality of Progress Monitoring Outcomes

ERIC Educational Resources Information Center

Christ, Theodore J.; Zopluoglu, Cengiz; Long, Jeffery D.; Monaghen, Barbara D.

2012-01-01

Curriculum-based measurement of oral reading (CBM-R) is frequently used to set student goals and monitor student progress. This study examined the quality of growth estimates derived from CBM-R progress monitoring data. The authors used a linear mixed effects regression (LMER) model to simulate progress monitoring data for multiple levels of…

Secondary Coronary Artery Vasospasm Promotes Cardiomyopathy Progression

PubMed Central

Wheeler, Matthew T.; Korcarz, Claudia E.; Collins, Keith A.; Lapidos, Karen A.; Hack, Andrew A.; Lyons, Matthew R.; Zarnegar, Sara; Earley, Judy U.; Lang, Roberto M.; McNally, Elizabeth M.

2004-01-01

Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of γ-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of γ-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated γ-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, γ-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 ± 13.3% treated versus 37.4 ± 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 ± 27.9 cm/second versus 92.8 ± 22.7 cm/second), and cardiac index (1.06 ± 0.30 ml/minute/g versus 0.67 ± 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression. PMID:14982859

Randomized study combining interferon and glatiramer acetate in multiple sclerosis.

PubMed

Lublin, Fred D; Cofield, Stacey S; Cutter, Gary R; Conwit, Robin; Narayana, Ponnada A; Nelson, Flavia; Salter, Amber R; Gustafson, Tarah; Wolinsky, Jerry S

2013-03-01

A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. Copyright © 2013 American Neurological Association.

Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma.

PubMed

Somasundaram, Kumaravel; Reddy, Sreekanth P; Vinnakota, Katyayni; Britto, Ramona; Subbarayan, Madhavan; Nambiar, Sandeep; Hebbar, Aparna; Samuel, Cini; Shetty, Mitesh; Sreepathi, Hari Kishore; Santosh, Vani; Hegde, Alangar Sathyaranjandas; Hegde, Sridevi; Kondaiah, Paturu; Rao, M R S

2005-10-27

Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaete-scute complex-like 1 (Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM.

Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.

PubMed

Niesvizky, Ruben; Mark, Tomer M; Ward, Maureen; Jayabalan, David S; Pearse, Roger N; Manco, Megan; Stern, Jessica; Christos, Paul J; Mathews, Lena; Shore, Tsiporah B; Zafar, Faiza; Pekle, Karen; Xiang, Zhaoying; Ely, Scott; Skerret, Donna; Chen-Kiang, Selina; Coleman, Morton; Lane, Maureen E

2013-03-15

This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥ VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥ VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥ 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.

Creating a Progress-Monitoring System in Reading for Middle-School Students: Tracking Progress toward Meeting High-Stakes Standards

ERIC Educational Resources Information Center

Espin, Christine; Wallace, Teri; Lembke, Erica; Campbell, Heather; Long, Jeffrey D.

2010-01-01

In this study, we examined the reliability and validity of curriculum-based measures (CBM) in reading for indexing the performance of secondary-school students. Participants were 236 eighth-grade students (134 females and 102 males) in the classrooms of 17 English teachers. Students completed 1-, 2-, and 3-minute reading aloud and 2-, 3-, and…

Linear and Nonlinear Growth Models for Value-Added Assessment: An Application to Spanish Primary and Secondary Schools' Progress in Reading Comprehension

ERIC Educational Resources Information Center

Lopez-Martin, Esther; Kuosmanen, Timo; Gaviria, Jose Luis

2014-01-01

Value-added models are considered one of the best alternatives not only for accountability purposes but also to improve the school system itself. The estimates provided by these models measure the contribution of schools to students' academic progress, once the effect of other factors outside school control are eliminated. The functional form for…

Assessing the Progress of Gender Parity in Education through Achieving Millennium Development Goals: A Case Study of Quetta District Balochistan

ERIC Educational Resources Information Center

Rashid, Abdul; Bibi, Zainab; Din, Siraj ud

2012-01-01

Using secondary data of Government Schools and literacy department for 10 years that is 2000-2010, this paper assesses the progress on the issue of gender equality within the framework of education related Millennium Development Goals (MDG) in district Quetta. The assessment is based on the selected indicators of goals by applying descriptive…

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants

PubMed Central

Meah, Farah A.; DiMeglio, Linda A.; Greenbaum, Carla J.; Blum, Janice S.; Sosenko, Jay M.; Pugliese, Alberto; Geyer, Susan; Xu, Ping; Evans-Molina, Carmella

2016-01-01

Aims/hypothesis The incidence of type 1 diabetes is increasing at a rate of 3–5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk. To test this in the TrialNet Pathway to Prevention (PTP) cohort, we analysed the influence of BMI, weight status and insulin resistance on progression from single to multiple islet autoantibodies (Aab) and progression from normoglycaemia to diabetes. Methods HOMA1-IR was used to estimate insulin resistance in Aab-positive PTP participants. Cox proportional hazards models were used to evaluate the effects of BMI, BMI percentile (BMI%), weight status and HOMA1-IR on the progression of autoimmunity or the development of diabetes. Results Data from 1,310 single and 1,897 multiple Aab-positive PTP participants were included. We found no significant relationships between BMI, BMI%, weight status or HOMA1-IR and the progression from one to multiple Aabs. Similarly, among all Aab-positive participants, no significant relationships were found between BMI, weight status or HOMA1-IR and progression to diabetes. Diabetes risk was modestly increased with increasing BMI% among the entire cohort, in obese participants 13–20 years of age, and with increasing HOMA1-IR in adult Aab-positive participants. Conclusions/interpretation Analysis of the accelerator hypothesis in the TrialNet PTP cohort does not suggest a broad influence of metabolic variables on diabetes risk. Efforts to identify other potentially modifiable environmental factors should continue. PMID:26995649

Physiotherapy Rehabilitation for People With Progressive Multiple Sclerosis: A Systematic Review.

PubMed

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

2016-01-01

To assess the efficacy of physiotherapy interventions, including exercise therapy, for the rehabilitation of people with progressive multiple sclerosis. Five databases (Cochrane Library, Physiotherapy Evidence Database [PEDro], Web of Science Core Collections, MEDLINE, Embase) and reference lists of relevant articles were searched. Randomized experimental trials, including participants with progressive multiple sclerosis and investigating a physiotherapy intervention or an intervention containing a physiotherapy element, were included. Data were independently extracted using a standardized form, and methodologic quality was assessed using the PEDro scale. Thirteen studies (described by 15 articles) were identified and scored between 5 and 9 out of 10 on the PEDro scale. Eight interventions were assessed: exercise therapy, multidisciplinary rehabilitation, functional electrical stimulation, botulinum toxin type A injections and manual stretches, inspiratory muscle training, therapeutic standing, acupuncture, and body weight-supported treadmill training. All studies, apart from 1, produced positive results in at least 1 outcome measure; however, only 1 article used a power calculation to determine the sample size and because of dropouts the results were subsequently underpowered. This review suggests that physiotherapy may be effective for the rehabilitation of people with progressive multiple sclerosis. However, further appropriately powered studies are required. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Photoexcitation Cascade and Quantum-Relativistic Jets in Graphene

NASA Astrophysics Data System (ADS)

Lewandowski, Cyprian; Levitov, L. S.

2018-02-01

In Dirac materials linear band dispersion blocks momentum-conserving interband transitions, creating a bottleneck for electron-hole pair production and carrier multiplication in the photoexcitation cascade. Here we show that the decays are unblocked and the bottleneck is relieved by subtle many-body effects involving multiple off-shell e -h pairs. The decays result from a collective behavior due to simultaneous emission of many soft pairs. We discuss characteristic signatures of the off-shell pathways, in particular the sharp angular distribution of secondary carriers, resembling relativistic jets in high-energy physics. The jets can be directly probed using solid-state equivalent of particle detectors. Collinear scattering enhances carrier multiplication, allowing for emission of as many as ˜10 secondary carriers per single absorbed photon.

Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers.

PubMed

Kruger, Thomas E; Miller, Andrew H; Godwin, Andrew K; Wang, Jinxi

2014-02-01

The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma.

PubMed

Burton, J H; Garrett-Mayer, E; Thamm, D H

2013-12-01

Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization. © 2012 Blackwell Publishing Ltd.

[Research progress in the role of aquaproin-4 and inward rectifying potassium channel 4.1 in spinal cord edema].

PubMed

Chen, Tiege; Dang, Yuexiu; Wang, Ming; Zhang, Dongliang; Guo, Yongqiang; Zhang, Haihong

2018-05-28

Spinal edema is a very important pathophysiological basis for secondary spinal cord injury, which affects the repair and prognosis of spinal cord injury. Aquaporin-4 is widely distributed in various organs of the body, and is highly expressed in the brain and spinal cord. Inward rectifying potassium channel 4.1 is a protein found in astrocytes of central nervous system. It interacts with aquaporins in function. Aquaporin-4 and inward rectifying potassium channel 4.1 play an important role in the formation and elimination of spinal cord edema, inhibition of glial scar formation and promotion of excitotoxic agents exclusion. The distribution and function of aquaporin-4 and inward rectifying potassium channel 4.1 in the central nervous system and their expression after spinal cord injury have multiple effects on spinal edema. Studies of aquaporin-4 and inward rectifying potassium channel 4.1 in the spinal cord may provide new ideas for the elimination and treatment of spinal edema.

SECRETED KLOTHO AND CHRONIC KIDNEY DISEASE

PubMed Central

Hu, Ming Chang; Kuro-o, Makoto; Moe, Orson W.

2013-01-01

Soluble Klotho (sKl) in the circulation can be generated directly by alterative splicing of the Klotho transcript or the extracellular domain of membrane Klotho can be released from membrane-anchored Klotho on the cell surface. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23), sKl, acts as hormonal factor and plays important roles in anti-aging, anti-oxidation, modulation of ion transport, and Wnt signaling. Emerging evidence reveals that Klotho deficiency is an early biomarker for chronic kidney diseases as well as a pathogenic factor. Klotho deficiency is associated with progression and chronic complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. In multiple experimental models, replacement of sKl, or manipulated up-regulation of endogenous Klotho protect the kidney from renal insults, preserve kidney function, and suppress renal fibrosis, in chronic kidney disease. Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease. PMID:22396167

Phenol homeostasis is ensured in vanilla fruit by storage under solid form in a new chloroplast-derived organelle, the phenyloplast

PubMed Central

Conéjéro, Geneviève

2014-01-01

A multiple cell imaging approach combining immunofluorescence by confocal microscopy, fluorescence spectral analysis by multiphotonic microscopy, and transmission electron microscopy identified the site of accumulation of 4-O-(3-methoxybenzaldehyde) β-d-glucoside, a phenol glucoside massively stockpiled by vanilla fruit. The glucoside is sufficiently abundant to be detected by spectral analysis of its autofluorescence. The convergent results obtained by these different techniques demonstrated that the phenol glucoside accumulates in the inner volume of redifferentiating chloroplasts as solid amorphous deposits, thus ensuring phenylglucoside cell homeostasis. Redifferentiation starts with the generation of loculi between thylakoid membranes which are progressively filled with the glucoside until a fully matured organelle is obtained. This peculiar mode of storage of a phenolic secondary metabolite is suspected to occur in other plants and its generalization in the Plantae could be considered. This new chloroplast-derived organelle is referred to as a ‘phenyloplast’. PMID:24683183

Phenol homeostasis is ensured in vanilla fruit by storage under solid form in a new chloroplast-derived organelle, the phenyloplast.

PubMed

Brillouet, Jean-Marc; Verdeil, Jean-Luc; Odoux, Eric; Lartaud, Marc; Grisoni, Michel; Conéjéro, Geneviève

2014-06-01

A multiple cell imaging approach combining immunofluorescence by confocal microscopy, fluorescence spectral analysis by multiphotonic microscopy, and transmission electron microscopy identified the site of accumulation of 4-O-(3-methoxybenzaldehyde) β-d-glucoside, a phenol glucoside massively stockpiled by vanilla fruit. The glucoside is sufficiently abundant to be detected by spectral analysis of its autofluorescence. The convergent results obtained by these different techniques demonstrated that the phenol glucoside accumulates in the inner volume of redifferentiating chloroplasts as solid amorphous deposits, thus ensuring phenylglucoside cell homeostasis. Redifferentiation starts with the generation of loculi between thylakoid membranes which are progressively filled with the glucoside until a fully matured organelle is obtained. This peculiar mode of storage of a phenolic secondary metabolite is suspected to occur in other plants and its generalization in the Plantae could be considered. This new chloroplast-derived organelle is referred to as a 'phenyloplast'. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Integrated Structural Biology for α-Helical Membrane Protein Structure Determination.

PubMed

Xia, Yan; Fischer, Axel W; Teixeira, Pedro; Weiner, Brian; Meiler, Jens

2018-04-03

While great progress has been made, only 10% of the nearly 1,000 integral, α-helical, multi-span membrane protein families are represented by at least one experimentally determined structure in the PDB. Previously, we developed the algorithm BCL::MP-Fold, which samples the large conformational space of membrane proteins de novo by assembling predicted secondary structure elements guided by knowledge-based potentials. Here, we present a case study of rhodopsin fold determination by integrating sparse and/or low-resolution restraints from multiple experimental techniques including electron microscopy, electron paramagnetic resonance spectroscopy, and nuclear magnetic resonance spectroscopy. Simultaneous incorporation of orthogonal experimental restraints not only significantly improved the sampling accuracy but also allowed identification of the correct fold, which is demonstrated by a protein size-normalized transmembrane root-mean-square deviation as low as 1.2 Å. The protocol developed in this case study can be used for the determination of unknown membrane protein folds when limited experimental restraints are available. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Long Winding Road to Transplant: How Sarcopenia and Debility Impact Morbidity and Mortality on the Waitlist.

PubMed

Bhanji, Rahima A; Carey, Elizabeth J; Yang, Liu; Watt, Kymberly D

2017-10-01

Frailty and sarcopenia are common complications of cirrhosis. Frailty has been described as an increased susceptibility to stressors secondary to a cumulative decline in physiologic reserve; this decline occurs with aging or is a result of the disease process, across multiple organ systems. Sarcopenia, a key component of frailty, is defined as progressive and generalized loss of skeletal muscle mass and strength. The presence of either of these complications is associated with increased morbidity and mortality, as these are tightly linked to decompensation and increased complication rates. Recognition of these entities is critical. Studies have shown improvement in muscle strength and function lead to reduced mortality, suggesting both frailty and sarcopenia are modifiable risk factors. In this review we outline the prevalence of frailty and sarcopenia in cirrhosis and the impact on clinical outcomes such as decompensation, hospitalization, and mortality. Existing and potential novel therapeutic approaches for frailty and sarcopenia are also reviewed. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Relationship between Multiple Intelligence, Reading Proficiency, and Implementing Motivational Strategies: A Study of Iranian Secondary Students

ERIC Educational Resources Information Center

Fayazi-Nasab, Ensieh; Ghafournia, Narjes

2016-01-01

There exist many factors, affecting reading ability. Multiple intelligence and motivational strategies are among the factors that seem to make significant contribution to the reading process. Thus, the present study probed the probable significant relation between Iranian language learners' multiple intelligences and reading ability. The study…

The Relevance of Depressive Symptoms and Social Support to Disability in Women with Multiple Sclerosis or Fibromyalgia

ERIC Educational Resources Information Center

Phillips, Lorraine J.

2010-01-01

Multiple sclerosis and fibromyalgia syndrome may spur substantial disability for those affected. Using structural equation modeling, this secondary analysis examined predictors of disability in women with multiple sclerosis (n = 118) and fibromyalgia syndrome (n = 197) recruited for separate wellness studies. Greater functional limitations, lower…

A gatekeeping procedure to test a primary and a secondary endpoint in a group sequential design with multiple interim looks.

PubMed

Tamhane, Ajit C; Gou, Jiangtao; Jennison, Christopher; Mehta, Cyrus R; Curto, Teresa

2018-03-01

Glimm et al. (2010) and Tamhane et al. (2010) studied the problem of testing a primary and a secondary endpoint, subject to a gatekeeping constraint, using a group sequential design (GSD) with K=2 looks. In this article, we greatly extend the previous results to multiple (K>2) looks. If the familywise error rate (FWER) is to be controlled at a preassigned α level then it is clear that the primary boundary must be of level α. We show under what conditions one α-level primary boundary is uniformly more powerful than another. Based on this result, we recommend the choice of the O'Brien and Fleming (1979) boundary over the Pocock (1977) boundary for the primary endpoint. For the secondary endpoint the choice of the boundary is more complicated since under certain conditions the secondary boundary can be refined to have a nominal level α'>α, while still controlling the FWER at level α, thus boosting the secondary power. We carry out secondary power comparisons via simulation between different choices of primary-secondary boundary combinations. The methodology is applied to the data from the RALES study (Pitt et al., 1999; Wittes et al., 2001). An R library package gsrsb to implement the proposed methodology is made available on CRAN. © 2017, The International Biometric Society.

Multiple trauma in children: critical care overview.

PubMed

Wetzel, Randall C; Burns, R Cartland

2002-11-01

Multiple trauma is more than the sum of the injuries. Management not only of the physiologic injury but also of the pathophysiologic responses, along with integration of the child's emotional and developmental needs and the child's family, forms the basis of trauma care. Multiple trauma in children also elicits profound psychological responses from the healthcare providers involved with these children. This overview will address the pathophysiology of multiple trauma in children and the general principles of trauma management by an integrated trauma team. Trauma is a systemic disease. Multiple trauma stimulates the release of multiple inflammatory mediators. A lethal triad of hypothermia, acidosis, and coagulopathy is the direct result of trauma and secondary injury from the systemic response to trauma. Controlling and responding to the secondary pathophysiologic sequelae of trauma is the cornerstone of trauma management in the multiply injured, critically ill child. Damage control surgery is a new, rational approach to the child with multiple trauma. The selection of children for damage control surgery depends on the severity of injury. Major abdominal vascular injuries and multiple visceral injuries are best considered for this approach. The effective management of childhood multiple trauma requires a combined team approach, consideration of the child and family, an organized trauma system, and an effective quality assurance and improvement mechanism.

The Swedish BioFINDER 2 Study

ClinicalTrials.gov

2018-04-16

Dementia; Alzheimer Disease; Parkinson Disease; Lewy Body Disease; Parkinson-Dementia Syndrome; Frontotemporal Degeneration; Semantic Dementia; Progressive Nonfluent Aphasia; Progressive Supranuclear Palsy; Corticobasal Degeneration; Multiple System Atrophy; Mild Cognitive Impairment

Highly charged ion secondary ion mass spectroscopy

DOEpatents

Hamza, Alex V.; Schenkel, Thomas; Barnes, Alan V.; Schneider, Dieter H.

2001-01-01

A secondary ion mass spectrometer using slow, highly charged ions produced in an electron beam ion trap permits ultra-sensitive surface analysis and high spatial resolution simultaneously. The spectrometer comprises an ion source producing a primary ion beam of highly charged ions that are directed at a target surface, a mass analyzer, and a microchannel plate detector of secondary ions that are sputtered from the target surface after interaction with the primary beam. The unusually high secondary ion yield permits the use of coincidence counting, in which the secondary ion stops are detected in coincidence with a particular secondary ion. The association of specific molecular species can be correlated. The unique multiple secondary nature of the highly charged ion interaction enables this new analytical technique.

Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease.

PubMed

Lindner, Moritz; Lambertus, Stanley; Mauschitz, Matthias M; Bax, Nathalie M; Kersten, Eveline; Lüning, Anna; Nadal, Jennifer; Schmitz-Valckenberg, Steffen; Schmid, Matthias; Holz, Frank G; Hoyng, Carel B; Fleckenstein, Monika

2017-02-01

To compare the disease course of retinal pigment epithelium (RPE) atrophy secondary to age-related macula degeneratio (AMD) and late-onset Stargardt disease (STGD1). Patients were examined longitudinally by fundus autofluorescence, near-infrared reflectance imaging, and best-corrected visual acuity (BCVA). Areas of RPE atrophy were quantified using semi-automated software, and the status of the fovea was evaluated based on autofluorescence and near-infrared reflectance images. Mixed-effects models were used to compare atrophy progression rates. BCVA loss and loss of foveal integrity were analyzed using Turnbull's estimator. A total of 151 patients (226 eyes) with RPE atrophy secondary to AMD and 38 patients (66 eyes) with RPE atrophy secondary to late-onset STGD1 were examined for a median time of 2.3 years (interquartile range, 2.7). Mean baseline age was 74.2 years (SD, 7.6) in AMD and 63.4 (SD, 9.9) in late-onset STGD1 (P = 1.1 × 10-7). Square root atrophy progression was significantly faster in AMD when compared with late-onset STGD1 (0.28 mm/year [SE, 0.01] vs. 0.23 [SE, 0.03]; P = 0.030). In late-onset STGD1, the median survival of the fovea was significantly longer when compared with eyes with AMD (8.60 vs. 3.35 years; P = 0.005) with a trend to a later BCVA loss of ≥3 lines (5.97 vs. 4.37 years; P = 0.382). These natural history data indicate differential disease progression in AMD versus late-onset STGD1. The results underline the relevance of refined phenotyping in elderly patients presenting with RPE atrophy in regard to prognosis and design of interventional trials.

Multisensor data fusion for integrated maritime surveillance

NASA Astrophysics Data System (ADS)

Premji, A.; Ponsford, A. M.

1995-01-01

A prototype Integrated Coastal Surveillance system has been developed on Canada's East Coast to provide effective surveillance out to and beyond the 200 nautical mile Exclusive Economic Zone. The system has been designed to protect Canada's natural resources, and to monitor and control the coastline for smuggling, drug trafficking, and similar illegal activity. This paper describes the Multiple Sensor - Multiple Target data fusion system that has been developed. The fusion processor has been developed around the celebrated Multiple Hypothesis Tracking algorithm which accommodates multiple targets, new targets, false alarms, and missed detections. This processor performs four major functions: plot-to-track association to form individual radar tracks; fusion of radar tracks with secondary sensor reports; track identification and tagging using secondary reports; and track level fusion to form common tracks. Radar data from coherent and non-coherent radars has been used to evaluate the performance of the processor. This paper presents preliminary results.

Enhanced secondary ion emission with a bismuth cluster ion source

NASA Astrophysics Data System (ADS)

Nagy, G.; Walker, A. V.

2007-04-01

We have investigated the mechanism of secondary ion yield enhancement using Bin+ (n = 1-6) primary ions and three different samples - dl-phenylalanine, Irganox 1010 and polystyrene - adsorbed on Al, Si and Ag substrates. The largest changes in secondary ion yields are observed for Bi2+ and Bi3+ primary ions. Smaller increases in secondary ion yield are found using Bi4+, Bi5+ and Bi6+ projectiles. The secondary ion yield enhancements are generally larger on Si than on Al. Using Bin+ structures obtained from density functional theory (DFT) calculations we demonstrate that the yield enhancements cannot be explained by an increase in the deposited energy density (energy per area) into the substrate. These data show that the mechanism of Bin+ sputtering is very similar to that for Aun+ primary ion beams. When a polyatomic primary ion strikes the substrate, its constituent atoms are likely to remain near to each other, and so a substrate atom can be struck simultaneously by multiple atoms. The action of these multiple concerted impacts leads to efficient energy transfer in the near surface region and an increase in the number of secondary ions ejected from the surface. Such concerted impacts involve one, two or three projectile atoms, which explains well the nonlinear yield enhancements observed going from Bi+ to Bi2+ to Bi3+.

Multiple Sclerosis

MedlinePlus

... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ...

The past, present and future of secondary metabolite research in the Dothideomycetes.

PubMed

Muria-Gonzalez, Mariano Jordi; Chooi, Yit-Heng; Breen, Susan; Solomon, Peter S

2015-01-01

The Dothideomycetes represents a large and diverse array of fungi in which prominent plant pathogens are over-represented. Species within the Cochliobolus, Alternaria, Pyrenophora and Mycosphaerella (amongst others) all cause diseases that threaten food security in many parts of the world. Significant progress has been made over the past decade in understanding how some of these pathogens cause disease at a molecular level. It is reasonable to suggest that much of this progress can be attributed to the increased availability of genome sequences. However, together with revealing mechanisms of pathogenicity, these genome sequences have also highlighted the capacity of the Dothideomycetes to produce an extensive array of secondary metabolites, far greater than originally thought. Indeed, it is now clear that we appear to have only scratched the surface to date in terms of the identification of secondary metabolites produced by these fungi. In the first half of this review, we examine the current status of secondary metabolite research in the Dothideomycetes and highlight the diversity of the molecules discovered thus far, in terms of both structure and biological activity. In the second part of this review, we survey the emerging techniques and technologies that will be required to shed light on the vast array of secondary metabolite potential that is encoded within these genomes. Experimental design, analytical chemistry and synthetic biology are all discussed in the context of how they will contribute to this field. © 2014 BSPP AND JOHN WILEY & SONS LTD.

Dynamic analysis of periodic vibration suppressors with multiple secondary oscillators

NASA Astrophysics Data System (ADS)

Ma, Jiangang; Sheng, Meiping; Guo, Zhiwei; Qin, Qi

2018-06-01

A periodic vibration suppressor with multiple secondary oscillators is examined in this paper to reduce the low-frequency vibration. The band-gap properties of infinite periodic structure and vibration transmission properties of finite periodic structure attached with secondary oscillators with arbitrary degree of freedom are thoroughly analyzed by the plane-wave-expansion method. A simply supported plate with a periodic rectangular array of vibration suppressors is considered. The dynamic model of this periodic structure is established and the equation of harmonic vibration response is theoretically derived and numerically examined. Compared with the simply supported plate without attached suppressors, the proposed plate can obtain better vibration control, and the vibration response can be effectively reduced in several frequency bands owing to the multiple band-gap property. By analyzing the modal properties of the periodic vibration suppressors, the relationship between modal frequencies and the parameters of spring stiffness and mass is established. With the numerical results, the design guidance of the locally resonant structure with multiple secondary oscillators is proposed to provide practical guidance for application. Finally, a practical periodic specimen is designed and fabricated, and then an experiment is carried out to validate the effectiveness of periodic suppressors in the reality. The results show that the experimental band gaps have a good coincidence with those in the theoretical model, and the low-frequency vibration of the plate with periodic suppressors can be effectively reduced in the tuned band gaps. Both the theoretical results and experimental results prove that the design method is effective and the structure with periodic suppressors has a promising application in engineering.

Approach to chronic wound infections.

PubMed

Leaper, D; Assadian, O; Edmiston, C E

2015-08-01

Infection is the likeliest single cause of delayed healing in healing of chronic open wounds by secondary intention. If neglected it can progress from contamination to colonization and local infection through to systemic infection, sepsis and multiple organ dysfunction syndrome, and it can be life-threatening. Infection in chronic wounds is not as easy to define as in acute wounds, and is complicated by the presence of biofilms. There is, as yet, no diagnostic for biofilm presence, but it contributes to excessive inflammation - through excessive and prolonged stimulation of nitric oxide, inflammatory cytokines and free radicals - and activation of immune complexes and complement, leading to a delay in healing. Control of biofilm is a key part of chronic wound management. Maintenance debridement and use of topical antimicrobials (antiseptics) are more effective than antibiotics, which should be reserved for treating spreading local and systemic infection. The continuing rise of antimicrobial resistance to antibiotics should lead us to reserve their use for these indications, as no new effective antibiotics are in the research pipeline. Antiseptics are effective through many mechanisms of action, unlike antibiotics, which makes the development of resistance to them unlikely. There is little evidence to support the theoretical risk that antiseptics select resistant pathogens. However, the use of antiseptic dressings for preventing and managing biofilm and infection progression needs further research involving well-designed, randomized controlled trials. © 2015 British Association of Dermatologists.

Protoplanetary disks in Taurus: Probing the role of multiplicity with ALMA observations

NASA Astrophysics Data System (ADS)

Laos, Stefan; Akeson, Rachel L.; Jensen, Eric L. N.

2017-01-01

We present results from an ALMA survey of single and multiple young systems in Taurus designed to probe how protoplanetary disk mass depends on both stellar mass and multiplicity. In observations taken in Cycles 0 and 2, we detect over 25 new disks. These detections include disks around stars in both single and multiple systems and are predominantly around lower mass stars with spectral types from M0 to M6. Combined with previous detections, these observations reveal a wide range of disk mass around both primary and companion stars, and allow us to test if the relation previously seen between disk and stellar mass continues at lower stellar masses. We find that within multiple systems the ratio of primary to secondary stellar mass is not correlated with the ratio of primary to secondary disk mass. In some cases, the secondary star hosts the more massive disk, contrary to theoretical predictions. We will discuss the implications of these results for the process of planet formation in multiple systems.This work makes use of the following ALMA data: ADS/JAO.ALMA#2011.0.00150.S. and ADS/JAO.ALMA#2013.1.00105.S. ALMA is a partnership of ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada) and NSC and ASIAA (Taiwan), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO and NAOJ. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.

Prevalence of "HIV/AIDS related" parental death and its association with sexual behavior of secondary school youth in Addis Ababa, Ethiopia: a cross sectional study.

PubMed

Menna, Takele; Ali, Ahmed; Worku, Alemayehu

2014-10-30

Human immunodeficiency virus infection is a global crisis that represents a serious health threat, particularly among younger people. Various studies show that both orphan and non-orphan adolescents and youths experience vulnerability to HIV. Nevertheless, the findings hitherto are mixed and inconclusive. The aim of this study, therefore, was to assess the prevalence of parental death and its association with multiple sexual partners among secondary school students for evidence based interventions. A cross-sectional study was conducted among secondary school youth in Addis Ababa, Ethiopia. A multistage sampling technique was used to select a representative sample of 2,169 school youths. Sexual health behavior related data were collected using self-administered questionnaire. Binary logistic regression was employed to examine the relation between parental death and multiple sexual partners. Among the 2,169 eligible study participants 1948 (90%) completed the self-administered questionnaires. Of those 1,182(60.7%) were females. The overall prevalence of parental death was 347(17.8%.) with 95% CI (16.2%, 19.6%). The HIV/AIDS proportionate mortality ratio was 28% (97/347).A multivariate logistic regression analysis showed that high HIV/AIDS related knowledge (AOR = 0.39; 95% CI, 0.18-0.84), positive attitude towards HIV prevention methods (AOR = 0.48; 95% CI, 0.23-0.97), being tested for HIV (AOR = 0.52; 95% CI, 0.31-0.87) and chewing Khat (AOR = 2.59; 95% CI,1.28-5.26)] were significantly associated with having multiple sexual partners among secondary school youths. Significant proportion of secondary school youths had lost at least one parent due to various causes. High knowledge of HIV/AIDS, positive attitude towards 'ABC' rules for HIV prevention, being tested for HIV and chewing khat are more likely to be factors associated with multiple sexual partnership among secondary school students in Addis Ababa.Therefore, the school based interventions against the HIV/AIDS epidemic should be strengthened with particular emphasis on the effects of HIV/AIDS related knowledge, attitude towards preventive measures, mechanisms for improving HIV Counseling and Testing coverage and the associated prevailing risk factors.

Zero-inflated modeling of fish catch per unit area resulting from multiple gears: Application to channel catfish and shovelnose sturgeon in the Missouri River

USGS Publications Warehouse

Arab, A.; Wildhaber, M.L.; Wikle, C.K.; Gentry, C.N.

2008-01-01

Fisheries studies often employ multiple gears that result in large percentages of zero values. We considered a zero-inflated Poisson (ZIP) model with random effects to address these excessive zeros. By employing a Bayesian ZIP model that simultaneously incorporates data from multiple gears to analyze data from the Missouri River, we were able to compare gears and make more year, segment, and macrohabitat comparisons than did the original data analysis. For channel catfish Ictalurus punctatus, our results rank (highest to lowest) the mean catch per unit area (CPUA) for gears (beach seine, benthic trawl, electrofishing, and drifting trammel net); years (1998 and 1997); macrohabitats (tributary mouth, connected secondary channel, nonconnected secondary channel, and bend); and river segment zones (channelized, inter-reservoir, and least-altered). For shovelnose sturgeon Scaphirhynchus platorynchus, the mean CPUA was significantly higher for benthic trawls and drifting trammel nets; 1998 and 1997; tributary mouths, bends, and connected secondary channels; and some channelized or least-altered inter-reservoir segments. One important advantage of our approach is the ability to reliably infer patterns of relative abundance by means of multiple gears without using gear efficiencies. ?? Copyright by the American Fisheries Society 2008.

Followership among UK Secondary School Teachers

ERIC Educational Resources Information Center

Francis, Andrew

2014-01-01

This paper reports the preliminary findings of an exploratory study which investigates the followership of longstanding, classroom-based school teachers working in the UK secondary education sector. Using Gronn's (1999) educational leadership formation model as a frame of reference, the study employs a multiple case study methodology with data…

Junior Secondary School Students' Conceptions about Plate Tectonics

ERIC Educational Resources Information Center

Mills, Reece; Tomas, Louisa; Lewthwaite, Brian

2017-01-01

There are ongoing calls for research that identifies students' conceptions about geographical phenomena. In response, this study investigates junior secondary school students' (N = 95) conceptions about plate tectonics. Student response data was generated from semi-structured interviews-about-instances and a two-tiered multiple-choice test…

Secondary-Progressive MS (SPMS)

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 ...

Effects of Single-Sex versus Co-Educational Classes and Schools on Gender Differences in Progress in Language and Mathematics Achievement

ERIC Educational Resources Information Center

Van de gaer, Eva; Pustjens, Heidi; Van Damme, Jan; De Munter, Agnes

2004-01-01

In this study, the effects of single-sex versus co-educational classes and schools on the progress in language and mathematics of boys and girls at the end of the second year of secondary education are investigated. Data from the Longitudinaal Onderzoek Secundair Onderwijs project are used. Multilevel analyses were carried out on a sample of…

Use of fundus autofluorescence images to predict geographic atrophy progression.

PubMed

Bearelly, Srilaxmi; Khanifar, Aziz A; Lederer, David E; Lee, Jane J; Ghodasra, Jason H; Stinnett, Sandra S; Cousins, Scott W

2011-01-01

Fundus autofluorescence imaging has been shown to be helpful in predicting progression of geographic atrophy (GA) secondary to age-related macular degeneration. We assess the ability of fundus autofluorescence imaging to predict rate of GA progression using a simple categorical scheme. Subjects with GA secondary to age-related macular degeneration with fundus autofluorescence imaging acquired at least 12 months apart were included. Rim area focal hyperautofluorescence was defined as percentage of the 500-μm-wide margin bordering the GA that contained increased autofluorescence. Rim area focal hyperautofluorescence on baseline fundus autofluorescence images was assessed and categorized depending on the extent of rim area focal hyperautofluorescence (Category 1: ≤33%; Category 2: between 33 and 67%; Category 3: ≥67%). Total GA areas at baseline and follow-up were measured to calculate change in GA progression. Forty-five eyes of 45 subjects were included; average duration of follow-up was 18.5 months. Median growth rates differed among categories of baseline rim area focal hyperautofluorescence (P = 0.01 among Categories 1, 2, and 3; P = 0.008 for Category 1 compared with Category 3, Jonckheere-Terpstra test). A simple categorical scheme that stratifies the amount of increased autofluorescence in the 500-μm margin bordering GA may be used to differentiate faster and slower progressors.

Posttraumatic Progressive Vertebral Hemangioma Induced by a Fracture

PubMed Central

Unal, Emre; Toktas, Zafer Orkun; Aker, Fugen Vardar; Akakın, Akın; Kilic, Türker

2017-01-01

The authors present an extremely rare case of an aggressive and progressive vertebral capillary hemangioma of the lumbar spine secondary to a trauma. A 40-year-old man who complained of back and leg pain due to a hemangioma of L1 that had begun a year after the fracture of the same vertebra was subsequently operated on. Due to the profuse bleeding, only a subtotal removal was possible. Histopathological diagnosis of the lesion revealed a capillary hemangioma. Postoperative control MRI taken at eight months showed that the lesion and destruction of the L1 vertebra were progressive. A second embolization procedure was performed and this time the hemangioma was totally removed via an anterior approach and corpectomy. Fusion was achieved by Th12-L2 graft and plaque. In the fourteenth year of follow-up, he was symptom-free and radiologically clear of this lesion. We propose that progressive hemangioma is extremely rare and that its cure is possible by total surgical removal of the lesion. This case is the second extradural capillary hemangioma secondary to spinal trauma ever to have been documented in English literature. The emergence of a hemangioma in a fractured vertebra suggests that its pathogenesis can be related to the deviation of the angiogenetic pathways from the normal healing process. PMID:28713608