Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

WITHDRAWN: Assessment of the inter-laboratory repeatability of gait analysis measurements in patients with multiple sclerosis.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Gold nanoparticle-based colorimetric biosensors.

Gold nanoparticles (AuNPs) provide excellent platforms for the development of colorimetric biosensors as they can be easily functionalised, displaying different colours depending on their size, shape and state of aggregation. In the last decade, a variety of biosensors have been developed to exploit the extent of colour changes as nano-particles (NPs) either aggregate or disperse, in the presence of analytes. Of critical importance to the design of these methods is that the behaviour of the systems has to be reproducible and predictable. Much has been accomplished in understanding the interactions between a variety of substrates and AuNPs, and how these interactions can be harnessed as colorimetric reporters in biosensors. However, despite these developments, only a few biosensors have been used in practice for the detection of analytes in biological samples. The transition from proof of concept to market biosensors requires extensive long-term reliability and shelf life testing, and modification of protocols and design features to make them safe and easy to use by the population at large. Developments in the next decade will see the adoption of user friendly biosensors for point-of-care and medical diagnosis as innovations are brought to improve the analytical performances and usability of the current designs. This review discusses the mechanisms, strategies, recent advances and perspectives for the use of AuNPs as colorimetric biosensors.

Haematopoietic stem cell transplantation in autoimmune diseases: From basic science to clinical practice.

Based on animal studies and serendipitous clinical cases, haematopoietic stem cell transplantation (HSCT) has been used since 1995 as a specific treatment for patients with severe treatment-resistant autoimmune disease (ADs). Despite other clinical developments for autoimmune diseases, including biological therapies, there has been an ongoing requirement for HSCT in some diseases and several thousand procedures have been registered in databases for a wide variety of diseases, predominantly for treatment with autologous HSCT. Currently, the main indications are multiple sclerosis, systemic sclerosis and Crohn's disease, which are supported by large series and randomised controlled trials (RCTs), whereas retrospective registry analyses support benefit in a range of rarer indications. Research into mechanisms of action has provided insight into how tolerance may be achieved with an intensive one-off treatment. In addition to the profound anti-inflammatory and immunosuppressive effects provided by the cytotoxic regimen, long-term responses in some diseases may be explained by 'resetting' the immune system through thymic reprocessing and generation of increased T-regulatory cell activity. This review aims to summarise the gradual evolution of HSCT in severe autoimmune diseases over the last 20 years, focussing on the recent publication of clinical and scientific studies, as well as evidence-based guidelines and recommendations.

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo.

GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron diseases. Homozygous gle1(-/-) mutant zebrafish display various aspects of LCCS, showing severe developmental abnormalities including motor neuron arborization defects and embryonic lethality. A previous gene expression study on spinal cord from LCCS fetuses indicated that oligodendrocyte dysfunction may be an important factor in LCCS. We therefore set out to investigate the development of myelinating glia in gle1(-/-) mutant zebrafish embryos. While expression of myelin basic protein (mbp) in hindbrain oligodendrocytes appeared relatively normal, our studies revealed a prominent defect in Schwann cell precursor proliferation and differentiation in the posterior lateral line nerve. Other genes mutated in LCCS have important roles in Schwann cell development, thereby suggesting that Schwann cell deficits may be a common factor in LCCS pathogenesis. These findings illustrate the potential importance of glial cells such as myelinating Schwann cells in motor neuron diseases linked to RNA processing defects.

Pragmatic intervention for increasing self-directed exercise behaviour and improving important health outcomes in people with multiple sclerosis: a randomised controlled trial.

BACKGROUND: Exercise programmes that can demonstrate evidence of long-lasting clinical effectiveness are needed for people with multiple sclerosis (PwMS). OBJECTIVE: The objective of this study was to assess the effects of a practically implemented exercise programme on self-directed exercise behaviour and important health outcomes in PwMS to nine months of follow-up. METHODS: We conducted a parallel-arm, randomised controlled trial: 120 PwMS (Expanded Disability Status Scale (EDSS) 1.0-6.5) randomised to a three-month exercise intervention plus usual care, or usual care only. Two supervised plus one home-exercise session (weeks 1-6) were followed by one supervised and two home-exercise sessions (weeks 7-12). Cognitive-behavioural techniques promoted long-term exercise behaviour change. Outcomes were blindly assessed at baseline and at three and nine months after randomisation. The primary outcome was self-reported exercise behaviour (Godin Leisure Time Exercise Questionnaire (GLTEQ)). Secondary outcomes included fatigue and health-related quality of life (HRQoL). RESULTS: The intervention increased self-reported exercise (9.6 points; 95% CI: 2.0 to 17.3 points; p = 0.01) and improved fatigue (p < 0.0001) and many HRQoL domains (p ≤ 0.03) at three months. The improvements in emotional well-being (p = 0.01), social function (p = 0.004) and overall quality of life (p = 0.001) were sustained for nine months. CONCLUSION: This pragmatic approach to implementing exercise increases self-reported exercise behaviour, improves fatigue and leads to a sustained enhancement of HRQoL domains in PwMS.

Cost effectiveness of a pragmatic exercise intervention (EXIMS) for people with multiple sclerosis: economic evaluation of a randomised controlled trial.

BACKGROUND: Exercise is a safe, non-pharmacological adjunctive treatment for people with multiple sclerosis but cost-effective approaches to implementing exercise within health care settings are needed. OBJECTIVE: The objective of this paper is to assess the cost effectiveness of a pragmatic exercise intervention in conjunction with usual care compared to usual care only in people with mild to moderate multiple sclerosis. METHODS: A cost-utility analysis of a pragmatic randomised controlled trial over nine months of follow-up was conducted. A total of 120 people with multiple sclerosis were randomised (1:1) to the intervention or usual care. Exercising participants received 18 supervised and 18 home exercise sessions over 12 weeks. The primary outcome for the cost utility analysis was the incremental cost per quality-adjusted life year (QALY) gained, calculated using utilities measured by the EQ-5D questionnaire. RESULTS: The incremental cost per QALY of the intervention was £10,137 per QALY gained compared to usual care. The probability of being cost effective at a £20,000 per QALY threshold was 0.75, rising to 0.78 at a £30,000 per QALY threshold. CONCLUSION: The pragmatic exercise intervention is highly likely to be cost effective at current established thresholds, and there is scope for it to be tailored to particular sub-groups of patients or services to reduce its cost impact.

Visual Outcomes from Shunting for Idiopathic Intracranial Hypertension.

A retrospective notes review was conducted for 50 consecutive patients who underwent shunt surgery for idiopathic intracranial hypertension (IIH). The decimal visual acuity and the mean radial degrees (MRD) of the I4e isopter of the Goldmann visual field were measured pre-operatively and after a mean follow-up period of 1123 days (range: 13-3551 days). A ventriculo-peritoneal shunt was the first procedure in 38 patients and a lumbo-peritoneal shunt in 12. The mean decimal visual acuity of the worse affected eye improved from 0.75 to 0.84, p = 0.011. The MRD score of the worse affected eye improved on average from 25.6° to 35.5°, p < 0.0001. In those with significant pre-operative visual impairment in their worse affected eye (defined as an MRD score ≤30°), the MRD score improved on average from 10.3° to 26.5°, p = 0.0008. The mean number of surgical procedures for each patient was 2.8 (range: 1-15). Taking all surgical procedures into account, post-operative complications were experienced by 30 patients. At last follow-up, 28 patients still complained of headache, 8 of whom had the intervention performed primarily for headache. Shunting can improve visual function in patients with IIH. There is significant post-operative morbidity and often the need for repeated procedures. Headache also commonly remains in these patients. There is a need for a randomised controlled trial of operative interventions in IIH. Sample size calculations for such a trial to treat significant vision loss are presented.

Pragmatic exercise intervention for people with multiple sclerosis (ExIMS trial): study protocol for a randomised controlled trial.

Exercise is an effective intervention for improving function, mobility and health-related quality of life in people with multiple sclerosis (PwMS). Questions remain however, regarding the effectiveness of pragmatic exercise interventions for evoking tangible and sustained increases in physical activity and long-term impact on important health outcomes in PwMS. Furthermore, dose-response relationships between exercise and health outcomes have not previously been reported in PwMS. These issues, and improved knowledge of cost effectiveness, are likely to influence key decisions of health policy makers regarding the implementation of exercise therapy as part of the patient care pathway for PwMS. Hence, the primary aim of this study is to investigate whether a 12-week tapered programme of supervised exercise, incorporating cognitive-behavioural techniques to facilitate sustained behaviour change, is effective for evoking improvements in physical activity and key health outcomes in PwMS over 9 months of follow-up. A total of 120 PwMS will be randomised (1:1) to either a 12-week pragmatic exercise therapy intervention or usual care control group. Participants will be included on the basis of a clinical diagnosis of MS, with an expanded disability status score (EDSS) between 1 and 6.5. Outcome measures, to be assessed before and after the intervention and 6 months later, will include physical activity, clinical and functional measures and health-related quality of life. In addition, the cost effectiveness of the intervention will be evaluated and dose-response relationships between physical activity and the primary/secondary outcomes in those with mild and more severe disease will be explored.

Isolation of enriched glial populations from post-mortem human CNS material by immuno-laser capture microdissection.

Isolating individual populations of cells from post-mortem (PM) central nervous system (CNS) tissue for transcriptomic analysis will provide important insights into the pathogenesis of neurodegenerative diseases. To date, research on individual CNS cell populations has been hindered by the availability of suitable PM material, unreliable sample preparation and difficulties obtaining individual cell populations. In this paper we report how rapid immunohistochemistry combined with laser capture microdissection (immuno-LCM) enables the isolation of specific cell populations from PM CNS tissue, thereby enabling the RNA profile of these individual cell types to be investigated. Specifically, we detail methods for isolating enriched glial populations (astrocytes, oligodendrocytes and microglia) and confirm this cell enrichment by polymerase chain reaction (PCR). In addition, the study details the numbers of each glial population required to obtain 50ng RNA, a suitable amount of starting material required to carry out microarray analysis that potentially may identify alterations of cell-specific genes and pathways associated with a range of neurodegenerative disorders.

CCL2 binding is CCR2 independent in primary adult human astrocytes.

Chemokines are low relative molecular mass proteins, which have chemoattractant actions on many cell types. The chemokine, CCL2, has been shown to play a major role in the recruitment of monocytes in central nervous system (CNS) lesions in multiple sclerosis (MS). Since resident astrocytes constitute a major source of chemokine synthesis including CCL2, we were interested to assess the regulation of CCL2 by astrocytes. We showed that CCL2 bound to the cell surface of astrocytes and binding was not modulated by inflammatory conditions. However, CCR2 protein was not detected nor was activation of the classical CCR2 downstream signaling pathways. Recent studies have shown that non-signaling decoy chemokine receptors bind and modulate the expression of chemokines at site of inflammation. Here, we show that the D6 chemokine decoy receptor is constitutively expressed by primary human adult astrocytes at both mRNA and protein level. In addition, CCL3, which binds to D6, but not CCL19, which does not bind to D6, displaced CCL2 binding to astrocytes; indicating that CCL2 may bind to this cell type via the D6 receptor. Our results suggest that CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the D6 decoy chemokine receptor. Therefore we propose that astrocytes are implicated in both the establishment of chemokine gradients for the migration of leukocytes into and within the CNS and in the regulation of CCL2 levels at inflammatory sites in the CNS.

Central inflammation versus peripheral regulation in multiple sclerosis.

Th17 cells are a highly pro-inflammatory T-helper cell subset characterised by the expression of IL17. They have been implicated in a variety of allergic and autoimmune conditions. T-regulatory (Treg) cells, a subset of CD4 cells which express Foxp3, CD25, IL10 and TGFß, can suppress the activity of Th17 cells. In this study, we show that the circulating levels of Th17 and Treg cells in peripheral blood are correlated; furthermore, the expression of the pro-inflammatory cytokine IL17 and the anti-inflammatory cytokine IL10 by CD4 cells are also correlated. However, we found no clear correlation between cerebrospinal fluid (CSF) IL10 and IL17 cytokine levels in MS, approaching a negative correlation at the time of relapse, and an overall negative correlation between CSF IL17 and TGFß levels, suggesting a lack of central regulation of pro:anti-inflammatory balance in this demyelinating condition.

The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK.

BACKGROUND AND PURPOSE: The purpose of this study was to identify the incidence and prevalence of idiopathic intracranial hypertension (IIH) in Sheffield, UK. METHODS: A retrospective review of case notes was conducted to identify cases of IIH seen between 1 January 2007 and 31 December 2008. RESULTS: Sixteen (15 women and 1 man) new patients were identified to give an incidence within Sheffield of 1.56/100,000/year and 2.86/100,000/year for women. The incidence of IIH in obese women was 11.9/100,000/year. The prevalence of IIH was calculated as 10.9/100,000, and 85.7/100,000 in obese women. CONCLUSION: A higher incidence of IIH than previously reported UK data was found, which may be because of increasing obesity within the population, or improved case ascertainment.

GAD antibody-associated neurological illness and its relationship to gluten sensitivity.

BACKGROUND: The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases. METHODS: We used ELISA assays for anti-GAD and for serological markers of gluten sensitivity. Patients were recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Patients with gluten sensitivity were followed up after the introduction of a gluten-free diet and serological testing was repeated. RESULTS: Six of seven (86%) patients with SPS were positive for anti-GAD, mean titre 109 U/ml; This compared with 9/90 (11%) patients with idiopathic sporadic ataxia, mean titre 32 U/ml, 16/40 (40%) patients with gluten ataxia, mean titre 25 U/ml, and 6/10 patients with type 1 diabetes only, mean titre 8 U/ml. None of 32 patients with celiac disease only, and of 40 patients with genetic ataxia were positive for anti-GAD. The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement. CONCLUSION: These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.

Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study.

BACKGROUND: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing-remitting MS (RRMS) patients. OBJECTIVES: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. METHODS: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. RESULTS: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. CONCLUSIONS: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study.

Idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) is a condition which affects predominantly overweight women and is characterized by raised intracranial pressure without any identifiable pathology in the brain and with normal cerebrospinal fluid (CSF) composition. The cause of IIH is unclear and as such it remains a diagnosis of exclusion. Although the pathophysiology of IIH remains elusive, some observations have recently been added to our understanding of this, including the presence of transverse sinus stenosis on many patients and the possible role of leptin and inflammation in the disease pathogenesis. Headache is the most common symptom and papilloedema is the major clinical finding. Choices of medical treatment are limited to the use of diuretics particularly acetazolamide and encouragement of weight loss. Surgical therapies such as CSF diversion procedures and fenestration of the optic nerve may be necessary in some cases with persistent symptoms or progressive visual deterioration. While not life-threatening, IIH has a significant morbidity with up to 25% of patients developing visual impairment from optic atrophy. Visual surveillance is therefore vital. Long-term follow-up is recommended as the disease may worsen after an initial period of stability.

Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis.

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below pound3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.