Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils

Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b⁺ cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.     

Patient-Centered Framework for Rehabilitation Research in Outpatient Settings

Conducting high-quality clinical research is dependent on merging scientific rigor with the clinical environment. This is often a complex endeavor that may include numerous barriers and competing interests. Overcoming these challenges and successfully integrating clinical research programs into clinical practice settings serving rehabilitation outpatients is beneficial from both a logistical perspective (eg, supports efficient and successful research procedures) and the establishment of a truly patient-centered research approach. Leveraging our experience with navigating this research-clinical care relationship, this article (1) proposes the Patient-Centered Framework for Rehabilitation Research, a model for integrating patient-centered research in an outpatient clinical setting that incorporates a collaborative, team-based model encompassing patient-centered values, as well as strategies for recruitment and retention, with a focus on populations living with disabilities or chronic diseases; (2) describes application of this framework in a comprehensive specialty multiple sclerosis center with both general strategies and specific examples to guide adaptation and implementation in other settings; and (3) discusses the effect of the framework as a model in 1 center, as well as the need for additional investigation and adaptation for other populations. The 5 interconnected principles incorporated in the Framework and which prioritize patient-centeredness include identifying shared values, partnering with the clinical setting, engaging with the population, building relationships with individuals, and designing accessible procedures. The Patient-Centered Framework for Rehabilitation Research is a model presented as an adaptable roadmap to guide researchers in hopes of not only improving individual patients’ experiences but also the quality and relevance of rehabilitation research as a whole. Future investigation is needed to test the Framework in other settings.     

Work productivity loss among adults aged 18–64 years with Multiple Sclerosis in the United States: A propensity score matched study

BackgroundScarce data exists regarding United States (US) national-level work productivity loss among adults with Multiple Sclerosis (MS).ObjectiveTo address this significant knowledge gap, we examined the national-level productivity loss among adults (18≤ age ≤64 years) with MS compared to propensity score matched non-MS controls.MethodsWe adopted a retrospective, cross-sectional, matched cohort study design with pooled data from alternate years (2005/2007/2009/2011/2013/2015) of the Medical Expenditure Panel Survey (MEPS). We included adults who were employed and alive during the calendar year. Clinical Classification System code of “80” was used to identify individuals with MS. We matched adults with MS to non-MS adults utilizing propensity scores generated based on age, gender, and race/ethnicity using a greedy matching algorithm (8:1-digit matching). Missed workdays measured productivity loss of MEPS respondents. We selected Negative Binomial Regression (NBR) analysis as the count data model for this study. Analyses were conducted using SAS 9.4 and STATA 15.0 and accounted for the complex survey design of MEPS to generate US national-level estimates.ResultsThe final propensity-score matched sample consisted of 104 and 312 (unweighted) adults with and without MS, respectively. US national-level mean [Standard Error (SE)] annual missed workdays among individuals with MS [8.94 (SE:1.59)] was significantly higher (p = 0.001) compared to propensity score matched non-MS controls [3.15 (SE:0.40)]. After adjusting for several factors, NBR showed an approximately two-fold higher rate of missed work days among individuals with MS compared to propensity score matched non-MS controls (Incidence Rate Ratio: 1.98, 95% Confidence Interval: 1.18–3.33). Severity of pain, marital status, region, and hypertension also negatively impacted work productivity in this sample.ConclusionsIndividuals with MS in the US experience significantly higher productivity loss compared to propensity score matched non-MS controls. Interventions (e.g., improved management of MS symptoms) are warranted to reduce productivity loss among individuals with MS.     

Eficacia de la terapia con señales electromagnéticas pulsadas y transmitidas de manera dieléctrica monopolar en procesos dolorosos asociados a esclerosis múltiple. Estudio piloto

IntroductionPain is highly prevalent in patients with multiple sclerosis (MS); it is chronic in 50% of cases and is classified as nociceptive, neuropathic, or mixed-type. Pain affects quality of life, sleep, and the activities of daily living. Electrotherapy is an interesting alternative or complementary treatment in the management of pain in MS, with new innovations constantly appearing.Material and methodsThis study evaluates the effectiveness of treatment with monopolar dielectric transmission of pulsed electromagnetic fields (PEMF) for pain associated with MS. We performed a randomised, placebo-controlled clinical trial including 24 patients, who were assessed with the Brief Pain Inventory, the Multiple Sclerosis International Quality of Life questionnaire, the Beck Depression Inventory, and the Modified Fatigue Impact Scale.ResultsStatistically significant improvements were observed in maximum and mean pain scores, as well as in the impact of pain on work, personal relationships, and sleep and rest. Not significant differences were found between the treatment and placebo groups.ConclusionsTreatment with PEMF may be effective in reducing pain in patients with MS, although further research is necessary to confirm its effectiveness over placebo and to differentiate which type of pain may be more susceptible to this treatment.     

Antinuclear antibodies positivity is not rare during multiple sclerosis and is associated with relapsing status and IgG oligoclonal bands positivity

IntroductionAs an immune-mediated disease of the central nervous system, multifaceted aspects of a humoral immune response are widely described during multiple sclerosis (MS). However, the prevalence of different auto-antibodies, such as antinuclear antibodies (ANA), during MS is very variable and their clinical relevance remains controversial. Our aim was to evaluate the prevalence and clinical correlations of ANA positivity in South Tunisian MS patients.Material and methodsWe performed ANA screening using indirect immunofluorescence (IIF) on HEp-2 cells (Biosystems®) in 82 MS patients. For ANA positive samples (titer ≥1/160), anti-ds-DNA detection (IIF on Crithidia luciliae (Biosystems®)) and extractable nuclear antigen typing (immunodot (Euroimmun®)) were performed.ResultsANA were positive in 35/82 MS patients (42.7%). The titer was ≥ 1/320 in 16/35 patients. The antigenic specificity of ANA was identified in 7/35 patients. None of the patients had extra-neurological manifestations. No correlation was found between ANA and age, gender, MS course, disease duration, disability, annual relapse rate nor IgG index. ANA positivity was more frequent in patients with IgG oligoclonal bands (OCB) (47.1%) than in patients without IgG OCB (16,6%) (p = 0.049). Regarding disease activity, ANA positivity was significantly more frequent in patients with relapse (52.6%) than in patients in remission (25.9%) (p = 0.031).ConclusionOur results showed that ANA positivity in MS disease is not rare. This positivity was not associated with clinical expression of any connective tissue disease. ANA occurrence in MS was associated with IgG OCB+ profile and relapsing status, probably reflecting an ongoing immune dysregulation.     

Reliability of gait and dual-task measures in multiple sclerosis

BackgroundSingle-task (ST) and dual-task (DT) assessments are commonly used to evaluate motor and cognitive impairment in people with multiple sclerosis (MS). Although variability can influence repeated DT testing measures, the reliability of several DT variables over time has not been adequately explored. For instance, a third testing session has never been included to observe whether DT has a learning effect. DT cognition rate reliability has not yet been examined and dual-task cost (DTC), a widely used calculation for DT interpretation, has not been proven reliable.Research questionTo evaluate the reliability of ST and DT measures of gait and cognition over three test sessions.MethodsThis was a cross-sectional study involving 18 people with MS and 12 controls. Participants attended three test sessions, each one week apart. ST and DT (serial seven subtraction) gait variables, DTC, coefficient of variability (CV), and cognition rate were extracted and calculated using an instrumented walkway. Reliability was assessed using intraclass correlation coefficients (ICC) or Kendall’s coefficient of concordance (KCC; nonparametric test) and minimum detectable change (MDC); between-session learning effect was assessed using repeated measures ANOVA.ResultsICC/KCC values for ST and DT gait variables ranged from moderate to excellent (0.50-0.99). However, reliability for DT stride width and cognition rate was lower in controls. In general, DTC and CV variables had poor ICCs and high MDC values (49.19–1478.67 %), although some DTC variables had moderate or higher reliability in controls. Cognition rate was reliable in both MS (ICC 0.91) and controls (ICC 0.84). A learning effect between sessions was observed for DT velocity in both groups and for DTC cadence in people with MS.SignificanceST and DT gait measures as well as DT cognition rate are reliable outcomes for repeated testing, while DTC and CV variables may not be suitable for long-term monitoring.     

肌萎缩侧索硬化案

肌萎缩侧索硬化症(ALS)是一种常见的上、下运动神经元同时损害的一种疾病,临床常见肢体无力、肌肉萎缩等症状。属中医学“痿证”范畴,本例验案患者双上肢及左下肢活动无力伴肌肉萎缩2年余,加重半年,伴随肌张力增高、反射亢进等症状,辨证属肝肾亏虚型痿证,临床以针刺治疗为主,配合静脉注射、穴位注射以补益肝肾,养血柔筋,疗效显著。     

Kombucha tea ameliorates experimental autoimmune encephalomyelitis in mouse model of multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis (MS), in which an inflammatory demyelination and axonal damage occurs. Kombucha tea is a fermented beverage made from kombucha mushroom, brewed tea, and sugar. In recent years kombucha tea has attracted interest due to its pharmacological properties like antioxidant effects. The aim of the present research was to test the therapeutic effect of kombucha tea in EAE. We induced EAE model in 18 female C57BL/6 mice by inoculation of myelin oligodendrocyte glycoprotein-35-55 (MOG_35-55) in complete Freund’s adjuvant emulsion. Then, in order to ameliorate EAE symptoms, we used kombucha tea. During the course of study clinical evaluation was assessed, and on the day 21 post-immunization, for evaluation of nitric oxide (NO), total antioxidants capacity and tumor necrosis factor-alpha (TNF-α), blood samples were taken from the heart of mice. The mice were sacrificed and brains and cerebellums of mice were removed for histological analysis. Our findings demonstrated that kombucha tea had beneficial effects on EAE by lower incidence, attenuation in the severity, and also a delay in the onset of disease. Histological analysis showed that inflammatory criteria including the number of infiltrated immune cells and plaques as well as demyelination in kombucha tea dosed mice were significantly lower than the control group. Also, in comparison with control mice, the serum levels of NO and TNF-α in kombucha tea-treated mice were significantly decreased. Kombucha tea with its potential therapeutic effects and immunomodulatory properties might be proposed, after additional necessary tests and trials, for treatment of MS.