Qualitative Investigation of Exercise Perceptions and Experiences in People With Multiple Sclerosis Before, During, and After Participation in a Personally Tailored Exercise Program.

OBJECTIVE: To undertake a qualitative investigation of exercise perceptions and experiences in people with multiple sclerosis (PwMS) before, during, and after participation in a personally tailored program designed to promote long-term maintenance of self-directed exercise. DESIGN: Focus groups and semistructured telephone interviews. SETTING: University exercise science department close to the recruiting hospital. PARTICIPANTS: PwMS (N=33; mean age ± SD, 47.6±7.9y). INTERVENTIONS: Participants were recruited after participation in a randomized controlled exercise trial; all had been allocated to a 12-week exercise program comprising supervised and self-directed exercise sessions. MAIN OUTCOME MEASURES: Exercise perceptions and experiences before, during, and after participation in the program. RESULTS: Four themes emerged from the analysis: (1) the transition to inactivity; (2) lack of knowledge and confidence; (3) positive exercise experiences; and (4) perspectives on exercise adherence. CONCLUSIONS: Lack of confidence and exercise knowledge, coupled with negative perceptions about physical capabilities after an MS diagnosis, are clear barriers to exercise participation in PwMS. These issues are not being adequately addressed as part of the health care pathway or in community settings. Perceptions of improved posture, ability to overcome everyday difficulties, acute mood enhancements during and after exercise, and increased opportunities for social interaction were among the reported benefits of exercise participation. Despite the provision of a personally tailored exercise plan and use of cognitive behavioral strategies, self-directed exercise continued to present challenges to PwMS, and the importance of seeking cost-effective ways to maintain motivational support was implicit in participant responses.

Optimization of gold nanoparticle-based real-time colorimetric assay of dipeptidyl peptidase IV activity.

Dipeptidyl peptidase IV (DPP-IV also referred to as CD-26) is a serine protease enzyme with remarkable diagnostic and prognostic value in a variety of health and disease conditions. Herein, we describe a simple and real-time colorimetric assay for DPP-IV/CD-26 activity based on the aggregation of gold nanoparticles (AuNPs) functionalized with the peptide substrates: Gly-Pro-Asp-Cys (GPDC) or Val-Pro-ethylene diamine-Asp-Cys (VP-ED-DC). Cleavage of the substrates by DPP-IV resulted in aggregation of the AuNPs with accompanying color change in the solution from red to blue that was monitored using either a UV-visible spectrophotometer or by the naked eye. Factors, such as time course of the reaction, stability of the functionalized AuNPs and the structure of the substrate that influence the cleavage reaction in solution were investigated. The effects of potential interference from serum proteins (lysozyme, thrombin and trypsin) on the analytical response were negligible. The detection limits when GPDC or VP-EN-DC functionalized AuNPs were used for DPP-IV assay were 1.2U/L and 1.5U/L, respectively. The VP-EN-DC method was preferred for the quantitative determination of DPP-IV activity in serum because of its wide linear range 0-30U/L compared to 0-12U/L for the GPDC assay. Recoveries from serum samples spiked with DPP-IV activity, between 5 and 25U/L, and using the VP-EN-DC modified AuNPs method ranged between 83.6% and 114.9%. The two colorimetric biosensors described here are superior to other conventional methods because of their simplicity, stability, selectivity and reliability.

Alcohol-related cerebellar degeneration: not all down to toxicity?

BACKGROUND: Alcohol-related cerebellar degeneration is one of the commonest acquired forms of cerebellar ataxia. The exact pathogenic mechanisms by which alcohol leads to cerebellar damage remain unknown. Possible autoreactive immune mediated mechanisms have not been explored previously. In this study, we aim to investigate the potential role of alcohol-induced immune mediated cerebellar degeneration. METHODS: Patients with ataxia and a history of alcohol misuse were recruited from the Ataxia and Hepatology tertiary clinics at Sheffield Teaching Hospitals NHS Trust. We determined the pattern of cerebellar involvement both on clinical (SARA score) and imaging (MRI volumetry and MR spectroscopy) parameters. In addition, HLA genotyping, serological markers for gluten-related disorders and serological reactivity on rat cerebellar tissue using indirect immunohistochemistry were assessed. RESULTS: Thirty-eight patients were included in the study all of whom had ataxia. The gait (97 %), stance (89 %) and heel-shin slide (89 %) were the predominant SARA elements affected. MRI volumetric and spectroscopy techniques demonstrated significant structural, volumetric and functional deficits of the cerebellum with particular involvement of the cerebellar vermis. Circulating anti-gliadin antibodies were detected in 34 % patients vs. 12 % in healthy controls. Antibodies to transglutaminase 6 (TG6) were detected in 39 % of patients and 4 % of healthy control subjects. Using immunohistochemistry, Purkinje cell and/or granular layer reactivity was demonstrated in 71 % of patient sera. CONCLUSIONS: Alcohol induced tissue injury to the CNS leading to cerebellar degeneration may also involve immune mediated mechanisms, including sensitisation to gluten.

Participant recruitment into a randomised controlled trial of exercise therapy for people with multiple sclerosis.

BACKGROUND: The success of a clinical trial is often dependant on whether recruitment targets can be met in the required time frame. Despite an increase in research into the benefits of exercise in people with multiple sclerosis (PwMS), no trial has reported detailed data on effective recruitment strategies for large-scale randomised controlled trials. The main purpose of this report is to provide a detailed outline of recruitment strategies, rates and estimated costs in the Exercise Intervention for Multiple Sclerosis (ExIMS) trial to identify best practices for future trials involving multiple sclerosis (MS) patient recruitment. METHODS: The ExIMS researchers recruited 120 PwMS to participate in a 12-week exercise intervention. Participants were randomly allocated to either exercise or usual-care control groups. Participants were sedentary, aged 18-65 years and had Expanded Disability Status Scale scores of 1.0-6.5. Recruitment strategies included attendance at MS outpatient clinics, consultant mail-out and trial awareness-raising activities. RESULTS: A total of 120 participants were recruited over the course of 34 months. To achieve this target, 369 potentially eligible and interested participants were identified. A total of 60 % of participants were recruited via MS clinics, 29.2 % from consultant mail-outs and 10.8 % through trial awareness. The randomisation yields were 33.2 %, 31.0 % and 68.4 % for MS clinic, consultant mail-outs and trial awareness strategies, respectively. The main reason for ineligibility was being too active (69.2 %), whilst for eligible participants the most common reason for non-participation was the need to travel to the study site (15.8 %). Recruitment via consultant mail-out was the most cost-effective strategy, with MS clinics being the most time-consuming and most costly. CONCLUSIONS: To reach recruitment targets in a timely fashion, a variety of methods were employed. Although consultant mail-outs were the most cost-effective recruitment strategy, use of this method alone would not have allowed us to obtain the predetermined number of participants in the required time period, thus leading to costly extensions of the project or failure to reach the number of participants required for sufficient statistical power. Thus, a multifaceted approach to recruitment is recommended for future trials. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Registry number: ISRCTN41541516 ; date registered: 5 February 2009.

Pragmatic exercise intervention in people with mild to moderate multiple sclerosis: a randomised controlled feasibility study.

BACKGROUND: People with Multiple Sclerosis (PwMS) are less physically active than the general population and pragmatic approaches designed to equip them with the skills and confidence to participate in long-term physical activity are required. OBJECTIVE: The objective of this study was to determine the feasibility of a pragmatic exercise intervention in PwMS. METHODS: A voluntary sample of 30 PwMS (male n = 4, female n = 26; mean age = 40 years; range = 24-49 years), with mild to moderate disability (EDSS ≤ 5.5), were recruited from eligible participants attending outpatient clinics. A total of 28 participants were randomised to a 10 week pragmatic exercise intervention (2× supervised and 1× home-based session per week) or usual care. Clinical, functional and quality of life (MSQoL-54) outcomes were assessed at baseline, immediately and 3 months after the intervention. RESULTS: Attrition was low (2 participants lost to immediate follow-up and 4 participants lost to 3 month follow-up), with high compliance rates (>75% of all sessions). The intervention group achieved progression of exercise volume (24.3 ± 7.0 to 30.9 ± 5.5 min per session), intensity (60.4 ± 8.8 to 67.7 ± 6.9% HR max) and training impulse (min × average HR=training impulse/load [arbitrary units; AU]) (2600 ± 1105 to 3210 ± 1269AU) during the intervention, whilst significantly increasing(P = 0.050) their physical composite score (MSQOL-54) at 10 weeks and readiness to exercise (P = 0.003) at 3 months compared with usual care. CONCLUSION: This pragmatic intervention was feasible for PwMS, but further research is needed to assess its long-term impact on physical activity behaviour.

Transglutaminase 6 antibodies in the diagnosis of gluten ataxia.

OBJECTIVES: The previous finding of an immunologic response primarily directed against transglutaminase (TG)6 in patients with gluten ataxia (GA) led us to investigate the role of TG6 antibodies in diagnosing GA. METHODS: This was a prospective cohort study. We recruited patients from the ataxia, gluten/neurology, celiac disease (CD), and movement disorder clinics based at Royal Hallamshire Hospital (Sheffield, UK) and the CD clinic, Tampere University Hospital (Tampere, Finland). The groups included patients with idiopathic sporadic ataxia, GA, and CD, and neurology and healthy controls. All were tested for TG6 antibodies. Duodenal biopsies were performed in patients with positive serology. In addition, biopsies from 15 consecutive patients with idiopathic sporadic ataxia and negative serology for gluten-related disorders were analyzed for immunoglobulin A deposits against TG. RESULTS: The prevalence of TG6 antibodies was 21 of 65 (32%) in idiopathic sporadic ataxia, 35 of 48 (73%) in GA, 16 of 50 (32%) in CD, 4 of 82 (5%) in neurology controls, and 2 of 57 (4%) in healthy controls. Forty-two percent of patients with GA had enteropathy as did 51% of patients with ataxia and TG6 antibodies. Five of 15 consecutive patients with idiopathic sporadic ataxia had immunoglobulin A deposits against TG2, 4 of which subsequently tested positive for TG6 antibodies. After 1 year of gluten-free diet, TG6 antibody titers were significantly reduced or undetectable. CONCLUSIONS: Antibodies against TG6 are gluten-dependent and appear to be a sensitive and specific marker of GA.

Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.

BACKGROUND: This study assessed the feasibility of a 12-week program of exercise, with and without intramuscular testosterone supplementation, in male patients with chronic heart failure (CHF) and low testosterone status and collected preliminary data for key health outcomes. METHODS: Male patients with CHF (n = 41, age 67.2 years, range 51-84 years) with mean ± SD testosterone levels of 10.7 ± 2.6 nmol/L (309 ± 76 ng/dL) were randomly allocated to exercise with testosterone or placebo groups. Feasibility was assessed in terms of recruitment, intervention compliance, and attrition. Outcomes included an incremental shuttle walk test, peak oxygen uptake, muscular strength, echocardiographic measures, N-terminal pro-brain natriuretic peptide, inflammatory markers, depression (Beck Depression Inventory), and health-related quality of life (Minnesota Living with Heart Failure Questionnaire and Medical Outcomes Study Short-Form). RESULTS: Attrition was 30% but with 100% compliance to exercise and injections in patients who completed the study. Similar improvements in shuttle walk test (18% vs 19%), body mass (-1.3 kg vs -1.0 kg), and hand grip strength (2.1 kg vs 2.5 kg) from baseline were observed in both groups. The exercise with testosterone group showed improvements from baseline in peak oxygen uptake (P < .01), Beck Depression Inventory (P < .05), leg strength (P < .05), and several Medical Outcomes Study Short-Form quality of life domains (P < .05), which were generally not apparent in the exercise with placebo group. Echocardiographic measures, N-terminal pro-brain natriuretic peptide, and inflammatory markers were mostly unchanged. CONCLUSIONS: This study shows for the first time that testosterone supplementation during a program of exercise rehabilitation is feasible and can positively impact on a range of key health outcomes in elderly male patients with CHF who have a low testosterone status.

Gluten sensitivity: from gut to brain.

Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.

Cytokines and chemokines in idiopathic intracranial hypertension.

BACKGROUND: The pathogenesis of idiopathic intracranial hypertension (IIH) remains unclear and as such it remains a diagnosis of exclusion. OBJECTIVES: To identify cerebrospinal fluid (CSF) and serum cytokine and chemokine profiles associated with IIH. METHOD: Semiquantitative assessment with cytokine antibody arrays was used to detect the relative expression of 42 different cytokines and chemokines in the CSF and serum of 8 IIH patients and 8 controls. Subsequently, quantitative assay with enzyme linked immunosorbent assay was performed for chemokine CCL2, interleukin-1 alpha (IL-1alpha), and leptin. RESULTS: Cytokine antibody array showed elevated levels of CCL2 in the CSF and CCL7, CCL8, IL-1alpha, and leptin levels in serum in IIH patients compared with controls. Subsequent quantitative assessment with enzyme linked immunosorbent assay showed significantly elevated CSF CCL2 in IIH patients compared with controls (P < .01) but there was no significant difference in leptin and IL-1alpha levels between the groups. CONCLUSION: This is the first report demonstrating differences in cytokine expression in the serum and CSF in IIH patients compared with controls. Since the pathogenesis of IIH is unclear, the heterogeneity of the cytokine expression reported here may help understand the pathogenesis of this condition.

Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase.

OBJECTIVE: Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity. Development of autoimmunity directed toward different members of the transglutaminase gene family could offer an explanation for the diversity in manifestations of gluten sensitivity. We have identified a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction. METHODS: Using recombinant human transglutaminases, we developed enzyme-linked immunosorbent assays and inhibition assays to analyze serum samples of patients with gluten-sensitive gastrointestinal and neurological disorders, and various control groups including unrelated inherited or immune conditions for the presence and specificity of autoantibodies. RESULTS: Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement. Such antibodies are absent in ataxia of defined genetic origin or in healthy individuals. Inhibition studies showed that in those patients with ataxia and enteropathy, separate antibody populations react with the two different transglutaminase isozymes. Furthermore, postmortem analysis of brain tissue showed cerebellar IgA deposits that contained transglutaminase 6. INTERPRETATION: Antibodies against transglutaminase 6 can serve as a marker in addition to human leukocyte antigen type and detection of anti-gliadin and anti-transglutaminase 2 antibodies to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease.

Gluten ataxia.

Gluten ataxia is an immune-mediated disease triggered by the ingestion of gluten in genetically susceptible individuals. It should be considered in the differential diagnosis of all patients with idiopathic sporadic ataxia. Early diagnosis and treatment with a gluten free diet can improve ataxia and prevent its progression. Readily available and sensitive markers of gluten ataxia include antigliadin antibodies. IgA deposits against TG2 in the small bowel and at extraintestinal sites are proving to be additional reliable and perhaps more specific markers of the whole spectrum of gluten sensitivity. They may also hold the key to its pathogenesis.

Cerebellar ataxia as a possible organ-specific autoimmune disease.

The purpose of this study was to investigate the possibility that autoimmunity is responsible for some cases of sporadic idiopathic ataxia. We prospectively investigated 400 patients with progressive ataxia and identified a group of patients with idiopathic sporadic ataxia. A comparison of the prevalence of autoimmune diseases, the autoimmunity linked HLA DQ2, and serum anticerebellar antibodies was made between patients with idiopathic sporadic and those with genetically characterized ataxia. Ninety-one of 400 (23%) patients with progressive ataxia had idiopathic sporadic ataxia. The prevalence of autoimmune diseases in this group was 47% as compared with 6% in the group of patients with genetic ataxias (P < 0.0001). The HLA DQ2 was found in 71% of patients with sporadic ataxia, in 34% in patients with genetic ataxia, and in 36% of healthy local population (P = 0.0005 by Chi squared test). Anticerebellar antibodies were detected in 12 out of 20 patients with idiopathic sporadic as opposed to one of 20 patients with genetic ataxia. The significantly higher prevalence of autoimmune diseases, HLA DQ2 and anti-cerebellar antibodies in patients with idiopathic sporadic ataxia compared to genetic ataxia supports the notion that autoimmunity may account for some cases of idiopathic sporadic cerebellar ataxia.

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment [ISRCTN08045231].

BACKGROUND: Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. METHODS/DESIGN: Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to approximately 25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. DISCUSSION: This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives.

Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics.

We previously have described a group of patients with gluten sensitivity presenting with ataxia (gluten ataxia) and suggested that this disease entity may account for a large number of patients with sporadic idiopathic ataxia. We have therefore investigated the prevalence of gluten sensitivity amongst a large cohort of patients with sporadic and familial ataxia and looked at possible genetic predisposition to gluten sensitivity amongst these groups. Two hundred and twenty-four patients with various causes of ataxia from North Trent (59 familial and/or positive testing for spinocerebellar ataxias 1, 2, 3, 6 and 7, and Friedreich's ataxia, 132 sporadic idiopathic and 33 clinically probable cerebellar variant of multiple system atrophy MSA-C) and 44 patients with sporadic idiopathic ataxia from The Institute of Neurology, London, were screened for the presence of antigliadin antibodies. A total of 1200 volunteers were screened as normal controls. The prevalence of antigliadin antibodies in the familial group was eight out of 59 (14%), 54 out of 132 (41%) in the sporadic idiopathic group, five out of 33 (15%) in the MSA-C group and 149 out of 1200 (12%) in the normal controls. The prevalence in the sporadic idiopathic group from London was 14 out of 44 (32%). The difference in prevalence between the idiopathic sporadic groups and the other groups was highly significant (P < 0.0001 and P < 0.003, respectively). The clinical characteristics of 68 patients with gluten ataxia were as follows: the mean age at onset of the ataxia was 48 years (range 14-81 years) with a mean duration of the ataxia of 9.7 years (range 1-40 years). Ocular signs were observed in 84% and dysarthria in 66%. Upper limb ataxia was evident in 75%, lower limb ataxia in 90% and gait ataxia in 100% of patients. Gastrointestinal symptoms were present in only 13%. MRI revealed atrophy of the cerebellum in 79% and white matter hyperintensities in 19%. Forty-five percent of patients had neurophysiological evidence of a sensorimotor axonal neuropathy. Gluten-sensitive enteropathy was found in 24%. HLA DQ2 was present in 72% of patients. Gluten ataxia is therefore the single most common cause of sporadic idiopathic ataxia. Antigliadin antibody testing is essential at first presentation of patients with sporadic ataxia.

Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10.

Inflammatory cell recruitment is an important step in the pathogenesis of autoimmune demyelinating diseases of the PNS. Chemokines might play a critical role in promoting leucocyte entry into the nervous system during immune-mediated inflammation. Here, we report the expression pattern of the chemokine receptors CCR-1, CCR-2, CCR-4, CCR-5 and CXCR-3 in sural nerve biopsies obtained from patients with classical Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy and various non-inflammatory neuropathies. A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies and quantitation of labelled mononuclear cells revealed significantly elevated cell counts compared with controls. CCR-1 and CCR-5 were primarily expressed by endoneurial macrophages, whereas CCR-2, CCR-4 and CXCR-3 could be localized to invading T lymphocytes. Quantitative analysis revealed that CXCR-3 was expressed at highest numbers by infiltrating T cells compared with the other receptors. Thus, expression and distribution of CXCR-3 suggest a specific role of this receptor in chemokine-mediated lymphocyte traffic into the inflamed PNS tissue. Therefore, we further analysed the expression of its ligands interferon-gamma-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-gamma (Mig). Significantly increased levels of IP-10 could be measured in the CSF of patients with inflammatory neuropathies, whereas no differences were observable for Mig. In situ hybridization for IP-10 mRNA mirrored the distribution of the cognate receptor within the inflamed PNS, and delineated endothelial cells as the primary cellular source of IP-10. Our results imply a pathogenic role for specific chemokine receptors and IP-10 in the genesis of inflammatory demyelinating neuropathies.