Multiple sclerosis and psychiatric disorders : comorbidity and sibling risk in a nationwide Swedish cohort

Background: Psychiatric disorders are known to be prevalent in Multiple Sclerosis (MS). Objective: To study comorbidity between MS and bipolar disorder, schizophrenia and depression in a nation-wide cohort and to determine whether shared genetic liability underlies the putative association. Methods: We identified ICD-diagnosed patients with MS (n=16,467), bipolar disorder (n=30,761), schizophrenia (n= 22,781) and depression (n=172,479) in the Swedish National Patient Register and identified their siblings in the Multi-Generation Register. The risk of MS was compared in psychiatric patients and in matched unexposed individuals. Shared familial risk between MS and psychiatric disorders was estimated by sibling comparison. Results: The risk of MS was increased in patients with bipolar disorder (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.6-2.2, p<0.0001) and depression (HR 1.9, 95% CI 1.7-2.0, p<0.0001). MS risk in schizophrenia was decreased (HR 0.6, 95% CI 0.4-0.9, p=0.005). The association between having a sibling with a psychiatric disorder and developing MS was not significant. Conclusion: We found a strong positive association between MS and bipolar disorder and depression that could not be explained by genetic liability. The unexpected negative association between MS and schizophrenia might be spurious or indicate possible protective mechanisms that warrant further exploration.Stockholm County CouncilThe Swedish Research CouncilKarolinska InstitutetAccepte

Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers.

The side chain oxidized oxysterol 24S-hydroxycholesterol (24-OH-chol) is formed almost exclusively in the brain, and there is a continuous passage of this oxysterol through the circulation to the liver. 27-Hydroxycholesterol (27-OH-chol) is produced in most organs and is also taken up by the liver. The 27-OH-chol-24-OH-chol ratio is about 0.1 in the brain and about 2 in the circulation. This ratio was found to be about 0.4 in cerebrospinal fluid (CSF) of asymptomatic patients, consistent with a major contribution from the circulation in the case of 27-OH-chol. In accordance with this, we demonstrated a significant flux of deuterium labeled 27-OH-chol from plasma to the CSF in a healthy volunteer. Patients with a defective blood-brain barrier were found to have markedly increased absolute levels (up to 10-fold) of both 27-OH-chol and 24-OH-chol in CSF, with a ratio between the two sterols reaching up to 2. There was a significant positive correlation between the levels of both oxysterols in CSF and the albuminCSF-albuminplasma ratio. The 27-OH-cholCSF-24-OH-cholCSF ratio was found to be about normal in patients with active multiple sclerosis and significantly increased in patients with meningitis, polyneuropathy, or hemorrhages. Results are discussed in relation to the possible use of 24-OH-cholCSF as a surrogate marker of central nervous system demyelination and/or neuronal death

Glucose metabolism in completed suicide: a forensic-pathological pilot study

Aim To determine whether antemortem blood levels of glycated hemoglobin (HbA1c) and glucose predict completed suicide and, by extension, whether markers of glucose metabolism might be associated with a prosuicidal trait or state. Method From consecutively performed autopsies, samples of blood and vitreous humor from 17 suicide victims and 27 non-suicide controls were compared with regard to levels of glucose, lactate, and HbA1c. Results Mean HbA1c was higher, and mean estimated blood glucose lower, among suicide victims, although tests revealed no significant differences (P = 0.171 and P = 0.395, respectively). HbA1c levels exceeding 48.0 mmol/mol, which were indicative of persistent hyperglycemia, were twice as common in suicide victims (59% vs 30%; P = 0.068). Conclusion The finding of this pilot study suggest that deranged glucose metabolism may reflect biological events antecedent to, or concomitant with, completed suicide, with the following clinical implications: recurring hyperglycemia due to defective glucose transport, which may give rise to depression and suicidal ideation, and elevated HbA1c levels, which may represent an assayable correlate to neurobiological conditions predisposing to suicide

A 1RM Strengthening and Exercise Programme for the Treatment of Knee Osteoarthritis: A Quality-Improvement Study

Background: The Kneefit programme is a 12-week strengthening and exercise programme, personalised using body-weight ratios, for people with knee osteoarthritis. Objectives and Design: This quality-improvement study was conducted to evaluate the effectiveness of the programme for managing symptomatic knee osteoarthritis. Methods: The Kneefit programme was delivered between 20 August 2013 and 7 January 2014 and included six weeks of supervised strengthening, balance, and cardiovascular exercise in a group at the local hospital, followed by six weeks of unsupervised exercise. Leg-press and knee-extension 1RM scores were assessed at baseline, six weeks, and twelve weeks. In addition, patient-reported outcome measures (Oxford Knee Score, EQ5D, Patient Specific Function Score (PSFS)) were assessed. Wilcoxon Signed Rank tests were used to evaluate the changes from week 1 to week 6 and week 12. Results: Thirty-six patients were included at baseline and at six weeks, and 31 patients completed their twelve-week assessment. Statistically significant improvements were found at 6 and 12 weeks for change for the Oxford Knee Score (median change: 4.0, IQR 4.0 to 9.0, p < 0.001 and 4.0, IQR 0 to 8.0, p < 0.001), EQ5D-5L (median change: 0.078, IQR 0.03 to 0.20, p < 0.001 and 0.071, IQR 0.02 to 0.25, p < 0.001) and the PSFS (median change: 1.3 IQR 0 to 2.6, p = 0.005 and 2.3 IQR −0.3 to 3.3, p = 0.016). In addition, significant improvements were found for 1RM leg-press and knee-extension scores on both the affected and unaffected legs. Conclusion: The Kneefit programme was successful at improving both functional and strength-related outcome measures in patients with knee osteoarthritis. Our findings suggest that tailoring strength exercises based on the 1RM strength-training principles is feasible in this population

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

Introduction: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. Trial registration ClinicalTrials.gov Identifier: NCT00099710

Tragicomic presentations of self : starring Phil Silvers as Bilko : the incomplete comic human

When a performer becomes over-associated with a particular, celebrated comic character can this lead to problems, not merely in terms of type-casting, but in creating confusions for the actor’s own perception of self? In instances where a comic creation is perceived to be an extension of the performer’s actual ‘self’, what dissonances in self construct may arise between the comic actor’s created persona and his/her own presentation of self? This article considers the nature of tensions created through the permeation of persona and person which can beset comedians who become closely identified with their particular mediated role. Can, indeed, over-association with their successful ‘signature’ comic role be seen to prove psychologically destabilising for certain performers whose own fragile, sense of identity becomes further compromised by presentation of their own most familiar and definitive, comic creations? Drawing specifically upon the career and comedy of Phil Silvers (aka ‘Sergeant ‘Bilko’), this article attempts to evaluate the forms of crises of identity that can arise between presentations of public and private selves for those performers who become, in effect, ‘public comic property’

Progress and prospects for event tourism research

This paper examines event tourism as a field of study and area of professional practice updating the previous review article published in 2008. In this substantially extended review, a deeper analysis of the field’s evolution and development is presented, charting the growth of the literature, focusing both chronologically and thematically. A framework for understanding and creating knowledge about events and tourism is presented, forming the basis which signposts established research themes and concepts and outlines future directions for research. In addition, the review article focuses on constraining and propelling forces, ontological advances, contributions from key journals, and emerging themes and issues. It also presents a roadmap for research activity in event tourism

Heritable modulators of the multiple sclerosis phenotype

Studies of families in which more than one case of multiple sclerosis (MS) occurs have demonstrated that shared genetic and/or environmental factors appear to modify clinical features of the disease, including rate of progression and disease course. We undertook in the present project to determine to what extent selected genetic factors constitute heritable determinants of the MS phenotype. We first reviewed the medical records of over 1200 MS patients, cataloguing clinico-demographic data, including disease course, age at onset, results of paraclinical examinations, and degree of disability. In Paper I, we found that carriers of the HLA class II specificity DR15-long known to confer susceptibility to MS-developed MS at an earlier age than noncarriers; that a second HLA class II specificity, DR17, is also positively associated with the risk of MS; that no HLA-DRB1 allele influences course or outcome in MS; and that differences in DR15 positivity rates, after stratification for diagnostic category and examinations results, seem to reflect a gradient of phenocopy contamination, with rates increasing in proportion to the degree of clinical or paraclinical, verification of the MS diagnosis. In Paper II, we show that the "head start" provided by carriage of DR15 is observed, independently, in patients with both bout-onset (BO; i.e., relapsing- remitting or secondary progressive) MS and primary progressive (PP) MS. In Paper III, we examined the possibility-first suggested in a report from Germany-that a rare variant of the CD45-encoding PTPRC gene is associated with nearly full penetrance of MS in a small subset of patients; we found, however, no difference in the occurrence of the variant between Swedish MS patients and controls. In Paper IV, we studied the impact of the Alzheimer-associated APOE gene on disability in MS by comparing genotype frequencies in our cohort's most extreme disability-stratified septiles. We found no significant differences between the benign-MS and severe-MS septiles; however, the risk conferred by the epsilon4 allele rose progressively upon comparison of carriage rates in more narrowly defined antipodal quantiles. In Paper V, we undertook to determine to what extent promoter-exon 1 haplotypes of CTLA4-a gene associated with susceptibility to several autoimmune diseases-influence age at onset, disease severity and disease course in MS. We found that CTLA4 haplotypes had no effect on age at onset or severity, but that deviations in haplotype frequencies could be observed in patients subgrouped by disease course. After subsequent analysis of a second, independent dataset, we confirmed that BOMS patients exhibited the same genotype and phenotype frequencies as controls, but that homozygosity for haplotype 2-a genotype associated with lower expression of CTLA4-conferred a more than two-fold risk of PPMS. In Paper VI, we characterized a consanguineous family of Middle Eastern origin exhibiting multiple cases of MS and performed a genome-wide screen, using microsatellite markers, on five affected and four unaffected family members now residing in Sweden. We found a haplotype spanning 43 centimorgans on the short arm of chromosome 9 for which four of five affected family members were homozygous and all unaffected family members heterozygous; however, the nonparametric logarithm- of -odds score for the region was no higher than a nonsignificant 2.3. Ironically, post-migration disease onset and a tendency towards date-of-onset (rather than age-at-onset) clustering seem to suggest the primacy of environmental factors over heritable ones in the etiology of MS in the kinship