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Background and purpose: Infections with human herpesvirus 6A (HHV‐6A) and Epstein–Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV‐6A associated risks of developing MS. Methods: In this nested case–control study, Swedish biobanks were accessed to find pre‐symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead‐based multiplex assay was used to determine serological response against EBV and HHV‐6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV‐6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6–2.7). Conclusions: This study suggests EBV infection after adolescence and age independent HHV‐6A infection as risk factors for MS. [ABSTRACT FROM AUTHOR]

Background and purpose: Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population‐based case–control study on this topic. Methods: Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time. Results: Compelling evidence was found for a link between major life events and risk of MS – most events significantly increased disease risk by 17%–30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development. Conclusion: Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS. [ABSTRACT FROM AUTHOR]

The prevalence of type 2 diabetes (T2D) is higher in black Africans than their European counterparts. This review summarizes the research exploring the pathogenesis of T2D in populations of African ancestry compared to white Europeans and shows that the pathogenesis differs by ethnicity. Black Africans present with a phenotype of low insulin sensitivity and hyperinsulinaemia as a result of increased insulin secretion and reduced hepatic insulin clearance. Whether hyperinsulinaemia precedes insulin resistance or is merely a compensatory mechanism is yet to be determined. Black Africans have lower visceral adipose tissue and ectopic fat deposition and greater peripheral (gluteo-femoral) fat deposition than their European counterparts. This suggests that black Africans are more sensitive to the effects of ectopic fat deposition, or alternatively, that ectopic fat is not an important mediator of T2D in black Africans. Importantly, ethnic disparities in T2D risk factors may be confounded by differences in sociocultural and lifestyle factors. Future longitudinal and dietary intervention studies, in combination with genetic analyses, are needed for a better understanding of the pathophysiology of T2D in black Africans. This will be key for effective prevention and management strategies. [ABSTRACT FROM AUTHOR]

Objective: Depression is associated with accelerated aging and age‐related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess the link between depressive symptoms, brain atrophy, and cortisol levels. Method: Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4‐year follow‐up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49). Results: Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression‐related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy. Conclusion: Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain. [ABSTRACT FROM AUTHOR]

Background and purpose: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision‐making process. Methods: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta‐analysis using a random‐effects model. The quality of evidence for each outcome was rated into four categories – very high, high, low and very low − according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. Results: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus. [ABSTRACT FROM AUTHOR]

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA- DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events. [ABSTRACT FROM AUTHOR]

Background Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons. Objective The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma ( IFNγ) production from immune cells in response to molecularly defined targets. Methods Cellular reactivity defined by IFNγ production was examined in blood from 38 ( HLA- DQB1*06:02+) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA- DQB1*06:02+ and 53 HLA- DQB1*06:02−) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal ( GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets ( CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue). Results IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 ( P = 0.0065) and streptodornase B protein ( P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine ( IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher ( P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls. Conclusion β-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response. [ABSTRACT FROM AUTHOR]

Background and purpose A reduced cancer risk amongst patients with multiple sclerosis ( MS) has been reported. Theoretically, this could represent a genuine reduction in risk or, alternatively, 'diagnostic neglect', where cancer is undiagnosed when symptoms are misattributed to MS. Objective Assess all-cause mortality risk following a cancer diagnosis in patients with MS compared with a cohort without MS. Patients A cohort of MS patients ( n = 19 364) and a cohort of the general population ( n = 192 519) were extracted from national Swedish registers from 1969 to 2005. All-cause mortality after cancer in MS was compared with the general population. Poisson regression analysis was conducted in the MS and non- MS cohorts separately. The models were adjusted for follow-up duration, year at entry, sex, region and socioeconomic index. The two cohorts were combined and differences in mortality risk were assessed using interaction testing. Results The adjusted relative risk (and 95% confidence interval) for all-cause mortality following a cancer diagnosis in MS patients (compared with MS patients without cancer) is 3.06 (2.86-3.27; n = 1768) and amongst those without MS 5.73 (5.62-5.85; n = 24 965). This lower magnitude mortality risk in the MS patients was confirmed by multiplicative interaction testing ( P < 0.001). Conclusions A consistent pattern of lower magnitude of all-cause mortality risk following cancer in MS patients for a range of organ-specific cancer types was found. It suggests that cancer diagnoses tend not to be delayed in MS and diagnostic neglect is unlikely to account for the reduced cancer risk associated with MS. The lower magnitude cancer risk in MS may be due to disease-associated characteristics or exposures. [ABSTRACT FROM AUTHOR]

Background and purpose The possible interaction between adolescent obesity and past infectious mononucleosis ( IM) was investigated with regard to multiple sclerosis ( MS) risk. Methods This report is based on two population-based case-control studies, one with incident cases (1780 cases, 3885 controls) and one with prevalent cases (4502 cases, 4039 controls). Subjects were categorized based on adolescent body mass index ( BMI) and past IM and compared with regard to occurrence of MS by calculating odds ratios with 95% confidence intervals ( CIs) employing logistic regression. A potential interaction between adolescent BMI and past IM was evaluated by calculating the attributable proportion due to interaction. Results Regardless of human leukocyte antigen ( HLA) status, a substantial interaction was observed between adolescent obesity and past IM with regard to MS risk. The interaction was most evident when IM after the age of 10 was considered (attributable proportion due to interaction 0.8, 95% CI 0.6-1.0 in the incident study, and attributable proportion due to interaction 0.7, 95% CI 0.5-1.0 in the prevalent study). In the incident study, the odds ratio of MS was 14.7 (95% CI 5.9-36.6) amongst subjects with adolescent obesity and past IM after the age of 10, compared with subjects with none of these exposures. The corresponding odds ratio in the prevalent study was 13.2 (95% CI 5.2-33.6). Conclusions An obese state both impacts the cellular immune response to infections and induces a state of chronic immune-mediated inflammation which may contribute to explain our finding of an interaction between adolescent BMI and past IM. Measures taken against adolescent obesity may thus be a preventive strategy against MS. [ABSTRACT FROM AUTHOR]

A correction to the article "Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up" that was published in the previous issue is presented.

Background and purpose Cardiovascular disease ( CVD) risk amongst multiple sclerosis ( MS) patients appears raised, but few studies have examined CVD risk amongst an unselected MS patient group. MS course may be relevant for CVD risk. Our aim was to assess CVD risk and variation by course in MS patients. Methods The Multiple Sclerosis Register identified 7667 patients who received an MS diagnosis between 1964 and 2005. They were matched by age, period, region and sex with 76 045 members of the general population without MS using Swedish registers. Poisson regression compared the two cohorts to estimate the relative risk for CVD, overall, as well as grouped and individual CVD diagnoses. Results MS patients had an increased adjusted relative risk (with 95% confidence intervals; number of MS cohort events) for CVD of 1.31 (1.22-1.41; n = 847), with some variation by course: relapsing−remitting 1.38 (1.17-1.62; n = 168); secondary progressive 1.30 (1.18-1.53; n = 405) and primary progressive 1.15 (0.93-1.41; n = 108). The association for the relapsing−remitting course was not significant after excluding the first year of follow-up. Overall incidence rates per 1000 person-years for CVD are 11.8 (11.06-12.66) for the MS cohort and 8.8 (8.60-9.05) for the non- MS cohort. The most pronounced association was for deep vein thrombosis: relapsing−remitting 2.16 (1.21-3.87; n = 14), secondary progressive 3.41 (2.45-4.75; n = 52) and primary progressive 3.57 (1.95-6.56; n = 15). MS was associated with ischaemic stroke but largely during the first year of follow-up. MS was associated with a decreased relative risk for angina pectoris and atrial fibrillation. Conclusions There is a significantly increased relative risk for CVD in MS, particularly for venous thromboembolic disorders in progressive MS, suggesting immobility as a possible factor. An increased frequency of ischaemic stroke in MS is most probably due to surveillance bias resulting from diagnostic investigations for MS. There is no increased relative risk for ischaemic heart disease in MS and atrial fibrillation appears to be less common than amongst the general population. [ABSTRACT FROM AUTHOR]

Objective The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/ SSA autoantibody-mediated congenital heart block. Subjects and Design Single nucleotide polymorphism ( SNP) genotyping of individuals in the Swedish Congenital Heart Block ( CHB) study population was performed. Low-resolution HLA-A, -Cw and - DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/ SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). Results A case-control comparison between index cases and population-based out-of-study controls ( n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 × 10−6 ( OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA- DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals ( P < 0.03 and P < 0.05, respectively), whilst HLA- DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children ( P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA- DRB1*04 transmission to affected offspring ( P < 0.02). Conclusions HLA- DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/ SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time. [ABSTRACT FROM AUTHOR]

The article reflects on treatment of multiple sclerosis (MS). It is said that individuals with MS are now diagnosed early is important for treatment with disease-modifying drugs (DMDs), but also for their care in general. It is also said that all current treatments and those that are about to enter the market act on systemic immunity.

During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini-review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof-of-principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α-synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union-funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between vaccination with Pandemrix and risk of selected neurological and immune-related diseases including narcolepsy. Design Population-based prospective cohort study using data from regional vaccination registries and national health registries. Setting Seven healthcare regions in Sweden comprising 61% of the Swedish population. Subjects Study population of 3 347 467 vaccinated and 2 497 572 nonvaccinated individuals (vaccination coverage ≈60%) followed between 2009 and 2011 for 6.9 million person-years after exposure and 6.0 million person-years without exposure. Main outcome measure and analysis First recorded diagnosis of neurological and immune-related diseases. Relative risks [hazard ratios ( HRs) with 95% confidence intervals ( CIs)] assessed using Cox regression, adjusted for covariates. Results For all selected neurological and immune-related outcomes under study, other than allergic vaccine reactions (for which we verified an expected increase in risk) and narcolepsy, HRs were close to 1.0 and always below 1.3. We observed a three-fold increased risk of a diagnosis of narcolepsy ( HR: 2.92, 95% CI: 1.78-4.79; that is, four additional cases per 100 000 person-years) in individuals ≤20 years of age at vaccination and a two-fold increase ( HR: 2.18, 95% CI: 1.00-4.75) amongst young adults between 21 and 30 years of age. The excess risk declined successively with increasing age at vaccination; no increase in risk was seen after 40 years of age. Conclusions For a large number of selected neurological and immune-related diseases, we could neither confirm any causal association with Pandemrix nor refute entirely a small excess risk. We confirmed an increased risk for a diagnosis of narcolepsy in individuals ≤20 years of age and observed a trend towards an increased risk also amongst young adults between 21 and 30 years. [ABSTRACT FROM AUTHOR]

Objectives Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids ( MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women. Subjects Ten healthy, nonsmoking postmenopausal women with a body mass index ( BMI) >27 (28-35) kg m−2 were included in the study. Interventions Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid ( IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy (1H- MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment ( HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. Results Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean −7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/ HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. Conclusions A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block. SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 x 10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02). CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time. [ABSTRACT FROM AUTHOR]

Background and purpose It has been hypothesized that exposure to anaesthetic agents, some of which are chemically related to organic solvents, may affect the risk of developing multiple sclerosis ( MS). The aim of this study was to estimate the influence of occupational exposure to anaesthetic agents on the risk for MS. We further aimed to investigate the impact of general anaesthesia and usage of nitrous oxide. Methods This report is based on two population-based, case-control studies, one with incident cases (1798 cases, 3907 controls) and one with prevalent cases (5216 cases, 4701 controls). Using logistic regression, the occurrence of MS among subjects who have been exposed to anaesthetic agents was compared with that of those who have never been exposed by calculating the odds ratio with a 95% confidence interval. Results No association was found between occupational exposure to anaesthetic agents and risk of developing MS, also general anaesthesia or usage of nitrous oxide had no impact on MS risk. Conclusions Neither occupational exposure to anaesthetic agents, nor general anaesthesia or usage of nitrous oxide has any impact on MS risk and is safe also for people with a genetic susceptibility to the disease. However, further studies would be valuable in order to clarify whether other forms of organic solvents contribute to the triggering of MS. [ABSTRACT FROM AUTHOR]

Background Chronic pain of neuropathic nature after spinal cord injury ( SCI) is common and its underlying mechanisms are poorly understood. Genes, as well as sex, have been implicated, but not thoroughly investigated in experimental genetic models for complex traits. We have previously found that inbred Dark- Agouti ( DA) rats develop more severe SCI pain-like behaviour than a major histocompatibility complex-congenic Piebald Virol Glaxo ( PVG)- RT1av1 strain in a model of photochemically induced SCI. Methods In this study, a genome-wide linkage study in an F2 cross between the susceptible DA and resistant PVG- RT1av1 strains was performed in order to explore the influence of genes and sex for SCI pain. Results A consistent finding was that female rats in parental, F1 and F2 generations displayed increased pain sensitivity at testing before injury and also developed mechanical hypersensitivity more rapidly and to a greater extent than male rats. In addition, we could identify three quantitative trait loci ( QTLs) associated with pain-like behaviour: a sex-specific QTL on chromosome 2, one on chromosome 15 and on chromosome 6. Animals carrying DA alleles at each of these loci were more susceptible to development of mechanical hypersensitivity compared with rats with PVG alleles. Conclusion This is the first whole genome QTL mapping of neuropathic pain-like behaviour in a model of SCI. The results provide strong support for a significant genetic and sex component in development of pain after SCI and provide the basis for further genetic dissection and positional cloning of the underlying genes. [ABSTRACT FROM AUTHOR]

Background: Both insufficient exposure to sunlight and vitamin D deficiency have been associated with an increased risk for multiple sclerosis (MS). An interaction between human leukocyte antigen HLA-DRB1*15 and vitamin D in MS was recently proposed. We investigated the association between previous exposure to ultraviolet radiation (UVR), vitamin D status at inclusion in the study, and MS risk including the interaction of these factors with HLA-DRB1*15. Methods: A population-based case-control study involving 1013 incident cases of MS and 1194 controls was performed in Sweden during 2005-2010. Subjects were classified according to their UVR exposure habits, vitamin D status, and HLA genotypes. The associations between different sun exposure habits/vitamin D levels and MS were calculated as odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. Potential interaction was evaluated by calculating the attributable proportion due to interaction. Results: Subjects with low UVR exposure had a significantly increased risk of MS compared with those who reported the highest exposure (OR 2.2, 95% CI 1.5-3.3). Similarly, subjects who had 25-hydroxy-vitamin D levels less than 50 nM/l had an increased risk for MS (OR 1.4, 95% CI 1.2-1.7). The association between UVR exposure and MS risk persisted after adjustment for vitamin D status. There was no interaction with HLA-DRB1*15 carriage. Conclusions: UVR and vitamin D seem to affect MS risk in adults independently of HLA-DRB1*15 status. UVR exposure may also exert a protective effect against developing MS via other pathways than those involving vitamin D. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) patients, with a second autoimmune disease after lymphocyte depletion, had elevated serum IL-21 before and after treatment which correlated to IL21 genotypes. In addition, the IL21 gene has been associated to several other autoimmune diseases. However, in a Spanish population there was no association to MS. Here, in a Swedish cohort (2090 MS cases and 1732 controls) 12 single nucleotide polymorphisms (SNPs) tagging IL21 were not associated to disease. There was no interaction with risk alleles of IL21R and HLA-DRB1*15. Lack of genetic association was confirmed in a meta-analysis with pooled data from the present study and the Spanish study. In conclusion, IL21 has not been shown to be a major risk gene for MS. [ABSTRACT FROM AUTHOR]

. Mälarstig A, Silveira A, Wågsäter D, Öhrvik J, Bäcklund A, Samnegård A, Khademi M, Hellenius M-L, Leander K, Olsson T, Uhlén M, de Faire U, Eriksson P, Hamsten A (Karolinska University Hospital; Institute of Environmental Medicine, Karolinska Institutet, Stockholm; KTH-Royal Institute of Technology, Stockholm, Sweden). Plasma CD93 concentration is a potential novel biomarker for coronary artery disease. J Intern Med 2011; 270: 229-236. Objectives. A common nonsynonymous single nucleotide polymorphism (SNP) in the CD93 gene (rs3746731, Pro541Ser) has been associated with risk of coronary artery disease (CAD). CD93 is a transmembrane glycoprotein, which is detectable in soluble form in human plasma. We investigated whether the concentration of soluble CD93 in plasma is related to risk of myocardial infarction (MI) and CAD, using a case-control study of premature MI ( n = 764) and a nested case-control analysis of a longitudinal cohort study of 60-year-old subjects (analysis comprising 844 of 4232 subjects enrolled at baseline). In addition, SNPs in the CD93 gene were studied in relation to plasma CD93 concentration and CD93 mRNA expression. Methods and Results. A sensitive and specific enzyme-linked immunosorbent assay was established for determination of the plasma CD93 concentration. Subjects were divided into three groups according to tertiles of the distribution of CD93 concentration. Lower odds ratios for risk of MI and incidence of CAD were observed in the middle CD93 tertile (142-173 μg L−1): odds ratio (95% confidence interval), 0.69 (0.49-0.97) and 0.61 (0.40-0.94), respectively. These associations were independent of traditional CAD risk factors. The minor allele of a SNP in the 3′ untranslated region of CD93 (rs2749812) was associated with increased plasma CD93 concentrations ( P = 0.03) and increased CD93 mRNA expression levels ( P = 0.02). Conclusion. The results of the present study suggest that the concentration of soluble CD93 in plasma is a potential novel biomarker for CAD, including MI. [ABSTRACT FROM AUTHOR]

Background: Natalizumab affects systemic cytokine expressions and clinical course in relapsing–remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. Methods: mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. Results: Natalizumab reduced CSF cell counts ( P < 0.0001). Tumor necrosis factor (TNF) and interferon-γ (IFN-γ) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-γ and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. Conclusions: Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy. [ABSTRACT FROM AUTHOR]

Introduction: An association between parental smoking and multiple sclerosis (MS) in offspring has been reported. This study examined whether maternal smoking during pregnancy is associated with MS in offspring. Methods: Swedish general population registers provided prospectively recorded information on maternal smoking during pregnancy. The study identified 143 cases with MS diagnosed by 2006 and 1730 matched controls. Subjects were born since 1982 and individually matched by year of birth, age, sex and region of residence. Conditional logistic regression assessed the association of maternal smoking with MS in offspring with adjustment for socioeconomic index. Results: Maternal smoking during pregnancy was not associated with MS in offspring, with an odds ratio (and 95% confidence interval) of 0.96 (0.65–1.44). When stratified by paediatric or later MS onset there was no association with maternal smoking in either stratum. Conclusion: It is unlikely that smoking during pregnancy represents a risk for early-onset MS amongst offspring. [ABSTRACT FROM AUTHOR]

The mRNA expression of eight different cytokines in peripheral blood mononuclear cells in 19 individuals with multiple sclerosis was determined at baseline and after 6 months of open-label treatment with natalizumab. Cellular expression of tumor necrosis factor α (TNFα) mRNA and number of cells secreting TNFα and interferon γ protein significantly increased over the 6 months. Kurtzke EDSS scores improved because of the resolution of relapses, but not fatigue severity scores. The observed increases in systemic proinflammatory cytokines by natalizumab treatment are discussed in relation to fatigue and systemic immunity. [ABSTRACT FROM AUTHOR]

Background It has been suggested that coeliac disease (CD) is associated with several neurological diseases. However, the evidence of such an association is inconclusive as earlier research has often been based on small numbers with retrospective data collection. Aim To use Cox regression to examine the risk of neurological disease in individuals with CD. Methods Through Swedish national registers we identified some 14 000 individuals with a diagnosis of CD (1964–2003) and 70 000 reference individuals matched for age, sex, calendar year and county. Results Coeliac disease was associated with later polyneuropathy [hazard ratio (HR) = 3.4; 95% CI = 2.3–5.1]. We found no statistically significant association between CD and subsequent multiple sclerosis (HR = 0.9; 95% CI = 0.3–2.3), Parkinson’s disease (HR = 1.2; 95% CI = 0.8–1.9), Alzheimer’s disease (HR = 1.5; 95% CI = 0.9–2.6), hereditary ataxia (HR = 1.3; 95% CI = 0.5–3.6), the symptom ataxia (HR = 1.9; 95% CI = 0.6–6.2), Huntington’s disease (HR = 1.7; 95% CI = 0.3–8.6), myasthenia gravis (HR = 0.8; 95% CI = 0.2–3.8) or spinal muscular atrophy (HR = 0.5; 95% CI = 0.1–3.8). Prior polyneuropathy was associated with subsequent CD (odds ratio = 5.4; 95% CI = 3.6–8.2). Conclusions The association between CD and polyneuropathy indicates shared risks. We suggest that individuals with polyneuropathy routinely undergo screening for CD. There is no notable association between CD and other neurological outcomes investigated in this study. [ABSTRACT FROM AUTHOR]

Content List ‐ Read more articles from the symposium: "Obesity and Type 2 Diabetes: Understanding the Role of Ethnicity". [ABSTRACT FROM AUTHOR]

Treatment with interferon (IFN)- β reduces clinical disease activity in multiple sclerosis (MS). Using flow cytometry, an enzyme-linked immunosorbent assay and a real-time polymerase chain reaction, we studied in vivo IFN- β-induced effects on CD4+ T-lymphocyte chemokine receptor expression as these influence central nervous system (CNS) transmigration and inflammation. At ‘steady state’ (≥1 day after the most recent IFN- β injection), IFN- β treatment increased CD4+ T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC chemokine receptor (CXCR)3 was unaltered. Conversely, at 9–12 h after the most recent IFN- β injection, CCR4, CCR5 and CCR7 expressions were unaltered, while CXCR3 expression was reduced. CD4+ T-cell surface expression of CCR4 was significantly lower in untreated MS patients compared with healthy volunteers. Of the plasma chemokines, only CXCL10 was increased by IFN- β treatment; CCL3, CCL4, CCL5 and CXCL9 were unaltered. CCR5 mRNA expression in blood mononuclear cells correlated with the expression of T-helper type 1 (Th1)-associated genes whereas CCR4 and CCR7 mRNA expression correlated with Th2 and immunoregulatory genes. In conclusion, IFN- β treatment caused ‘steady-state’ increases of several chemokine receptors relevant for CD4+ T-lymphocyte trafficking and function, possibly facilitating lymphocyte migration into the CNS. An important therapeutic effect of IFN- β treatment may be the normalization of a decreased Th2-related CD4+ T-cell CCR4 expression in MS patients. Surface chemokine receptor expression and CXCL10 varied according to the timing of blood sampling in relation to the most recent IFN- β injection. Thus, it is imperative to distinguish acute effects of IFN- β from steady-state effects. [ABSTRACT FROM AUTHOR]

Söderberg S, Stegmayr B, Stenlund H, Sjöström L-G, Ågren Å, Johansson L, Weinehall L, Olsson T (Umeå University, Umeå, Sweden). Leptin, but not adiponectin, predicts stroke in males. J Intern Med 2004; 256: 128–136. To test whether leptin and adiponectin are risk markers for a first-ever stroke. A nested case-referent study identified 276 cases with first-ever stroke (234 cases with ischaemic and 42 with haemorrhagic stroke). Prior to the stroke, they had participated in population-based health surveys in northern Sweden (median time between survey and stroke was 4.9 years). Referents were matched for sex, age, date and type of health survey, and geographical region. Putative risk markers for first-ever stroke, including blood pressure (BP), diabetes, smoking, body mass index (BMI), cholesterol, leptin, and adiponectin, were analysed by conditional logistic regression analysis. Increased BMI, high cholesterol and fasting glucose levels, diabetes mellitus and hypertension were found in future stroke patients. Whereas leptin levels were higher in male subjects ( P = 0.004), adiponectin did not differ between groups. A high leptin level independently predicted stroke in men (OR = 2.46; 95% CI 1.08–5.62) but not in women. Adiponectin levels did not predict stroke. Males with high leptin levels developed stroke faster than males with low leptin levels ( P = 0.0009), independently of traditional risk factors. Leptin may be an important link to the development of cerebrovascular disease in men, whereas adiponectin does not associate with future stroke. [ABSTRACT FROM AUTHOR]

Marklund N, Peltonen M, Nilsson TK, Olsson T (Uppsala University, Uppsala; University of Northern Sweden, Umeå; and Örebro University Hospital, Örebro; Sweden). Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke. J Intern Med 2004; 256: 15–21. Elevated cortisol levels are associated with confusion and poor outcome after stroke. Dehydroepiandrosterone sulphate (DS), the most abundant adrenal androgen may act as an anti-glucocorticoid. An altered regulation of these steroids may affect numerous brain functions, including neuronal survival. The purpose of this study was to investigate serum cortisol and DS levels and the cortisol/DS ratio early after stroke and relate our findings to the presence of disorientation and mortality. Patients with acute ischaemic stroke (n = 88, 56 men and 32 women) admitted to a stroke unit were investigated with repeated clinical assessments and scores for degree of confusion, extent of paresis and level of functioning. Serum cortisol (C) and DS were measured on day 1 and/or day 4. Data for 28-day and 1-year mortality are presented. A control group of 65 age-matched healthy individuals was used. Multivariate analyses of mortality rates in the different tertiles or sixtiles of serum cortisol were performed with logistic regression, adjusting for age, sex, diabetes and level of consciousness. There was no difference in serum cortisol levels on day 1 for stroke patients when compared with control group values. Initial cortisol levels were significantly higher in the patients with acute disorientation versus orientated patients (P < 0.05). Cortisol levels on day 1 were an independent predictor of 28-day mortality, and patients with low cortisol levels (<270 nmol L-1) and increased levels (>550 nmol L-1) both had an increased 1-year mortality. DS levels on day 1 were significantly elevated in stroke patients. Hypercortisolism is associated with cognitive dysfunction early after ischaemic stroke. High and low circulating cortisol levels are associated with increased mortality after stroke. DS levels were not associated with clinical outcome. [ABSTRACT FROM AUTHOR]

Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesis-driven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers. [ABSTRACT FROM AUTHOR]

Olsson T, Terent A, Lind L (University Hospital, Uppsala; The Research and Development Unit, Jamtland County Council, Östersund; and AstraZeneca R&D, Mölndal; Sweden). Rapid Emergency Medicine score: a new prognostic tool for in-hospital mortality in nonsurgical emergency department patients. J Intern Med 2004; 255: 579–587. To evaluate the predictive accuracy of the scoring system Rapid Acute Physiology score (RAPS) in nonsurgical patients attending the emergency department (ED) regarding in-hospital mortality and length of stay in hospital (LOS), and to investigate whether the predictive ability of RAPS could be improved by extending the system. Prospective cohort study. An adult ED of a 1200-bed university hospital. A total of 12 006 nonsurgical patients presenting to the ED during 12 consecutive months. For all entries to the ED, RAPS (including blood pressure, respiratory rate, pulse rate and Glasgow coma scale) was calculated. The RAPS system was extended by including the peripheral oxygen saturation and patient age (Rapid Emergency Medicine score, REMS) and this new score was calculated for each patient. The statistical associations between the two scoring systems and in-hospital mortality as well as LOS in hospital were examined. The REMS was superior to RAPS in predicting in-hospital mortality [area under receiver operating characteristic (ROC) curve 0.852 ± 0.014 SEM for REMS compared with 0.652 ± 0.019 for RAPS, P < 0.05]. An increase of 1-point in the 26-point REMS scale was associated with an OR of 1.40 for in-hospital death (95% CI: 1.36–1.45, P < 0.0001). Similar results were obtained in the major patient groups (chest pain, stroke, coma, dyspnoea and diabetes), in all age groups and in both sexes. The association between REMS and LOS was modest ( r = 0.47, P = 0.0001). The REMS was a powerful predictor of in-hospital mortality in patients attending the ED over a wide range of common nonsurgical disorders. [ABSTRACT FROM AUTHOR]

Central Nervous system (CNS)-autoreactive immune responses can exert neuro-protective effects, possibly mediated via the release of neurotrophic factors from infiltrating leucocytes. Herein, we analyzed neurotrophin and cytokine mRNA levels using TaqMan polymerase chain reaction in unstimulated peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients in remission and controls. We demonstrate that mRNA for brain-derived neurotrophic factor (BDNF), but not neurotrophin-3 or nerve growth factor (NGF), is readily detectable in PBMC and that levels in MS are increased by approximately 60% compared with patients with other neurological diseases or healthy subjects. These results provide additional evidence that a potentially neuroprotective facet of autoimmune inflammation is present in MS. [ABSTRACT FROM AUTHOR]

Objective: Hyperproinsulinaemia and hyperleptinaemia are interrelated features of the insulin resistance syndrome that are linked to the prospective risk of cardiovascular diseases. Whether the association between leptin and proinsulin is different between groups displaying different degrees of risk for cardiovascular diseases is not known. We therefore examined this association in men versus women and in pre- versus postmenopausal women from a population-based sample.Design and Subjects: Healthy subjects (n = 158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease population were studied with a cross-sectional design.Methods: Anthropometric measurements (body mass index and waist circumference) and oral glucose tolerance tests were performed. Enzyme-linked immunosorbent assays were used for the analyses of specific insulin and proinsulin, and radioimmunoassay for leptin. Insulin resistance and beta-cell function were calculated according to the homeostasis assessment model. Partial correlation coefficients adjusted for age and measures of adiposity were calculated and multiple linear regression analyses were performed with leptin as dependent variable.Results: In nonobese men and premenopausal women and in obese postmenopausal women, leptin was significantly associated with proinsulin after stratification for waist circumference. Furthermore, a multivariate analyses taking age and measures of adiposity into account, showed that high fasting proinsulin was a significant predictor of high leptin in these groups. In contrast, this association was lost with increasing central obesity in men and premenopausal women.Conclusions: This study shows that both the degree of adiposity and the hormonal milieu influence the association between circulating leptin and proinsulin in a normal population. Therefore, the insulin resistance syndrome seems to be characterized by lost association between leptin and proinsulin, which may be explained by dysfunction in the adipoinsular axis. [ABSTRACT FROM AUTHOR]

A potentially pathogenic expansion of T cells expressing T cell receptor (TCR) Vβ 5.2/5.3 has been demonstrated in patients with multiple sclerosis (MS). A humanized antibody (ATM-027) directed against these T cells has been developed to further investigate the role of this subpopulation of T cells in MS. The pharmacokinetics/dynamics and safety of ATM-027 (0.3–300 mg intravenously over 30 min) were investigated in 14 patients with MS. The effect of treatment on cytokine expression and autoreactivity to peptides of myelin basic protein (MBP) was also studied. ATM-027 was well tolerated and raised no safety concerns. Clearance of the antibody was low and elimination half-life was approximately 3 weeks. The majority of the target Vβ 5.2/5.3 expressing T cells were depleted for at least 18 months. The small remaining fraction of target cells showed a marked decrease in their TCR expression, which was recovered within 8 months. The numbers of peripheral blood mononuclear cells (PBMCs) with spontaneous expression of IFN-γ was decreased at 72 h and 8 weeks after treatment, whilst no clear effects on TNF-α , IL-4, IL-10, TGF-β expression were observed. There was also a significant decrease in the number of PBMCs producing IFN-γ in response to MBP peptide 80–102. We conclude that long-term depletion of T cells expressing defined Vβ subgroups in MS patients is feasible using selective immunotherapy. The selective depletion of Vβ 5.2/5.3 expressing T cells in this study resulted in a decrease in potentially disease promoting anti-MBP reactivity and pro-inflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that autoimmune reactions in the central nervous system (CNS) not only have detrimental consequences but can also be neuroprotective, and that this effect is mediated by the expression of neuronal growth factors by infiltrating leucocytes. Here we dissect these two phenomena in guinea pig myelin basic protein peptide (gpMBP 63–88)-induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Real-time TaqMan polymerase chain reaction (PCR) was used to measure mRNA for the nerve growth factors, brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3. As reference, the well-known proinflammatory mediator molecules interferon (IFN)-γ and tumour necrosis factor (TNF)-α were quantified. In whole lumbar cord tissue, both the nerve growth factors and the proinflammatory cytokines, IFN-γ and TNF-α, displayed similar expression patterns, peaking at the height of the disease. Among the infiltrating inflammatory cells isolated and sorted from the CNS, αβ+ /T-cell receptor (TCR)BV8S2+ , but not αβ+ /TCRBV8S2– , recognized the encephalitogenic MBP peptide. Interestingly, these two populations displayed contrasting expression patterns of nerve growth factors and proinflammatory cytokines with higher inflammatory cytokine mRNA levels in αβ+ /TCRBV8S2+ cells at all time intervals, whereas the levels of BDNF and NT3 were higher in αβ+ /TCRBV8S2– cells. We conclude that a potentially important neuroprotective facet of CNS inflammation dominantly prevails within other non-MBP peptide-specific lymphoid cells and that there are independent regulatory mechanisms for neurotrophin and inflammatory cytokine expression during EAE. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is simulated by various forms of experimental autoimmune encephalomyelitis, in which T cells, antibodies, cytokines and complementary factors interact with the central nervous system (CNS) myelin proteins and lead to inflammatory damage. We investigated the role of Fc receptors (FcRs), which link the cellular and humoral branches of the immune system, in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), using two different FcRγ knockout DBA/1 mice. The first knockout were the FcRγ chain-deficient mice, which lack FcγRI, FcγRIII and FcεRI, while the second knockout mice lack only FcγRII. The lack of FcγRII enhanced the disease susceptibility with associated increased CNS demyelination. While FcRγ+/+ DBA/1 mice also developed pronounced CNS infiltration and myelin destruction, FcRγ-/- littermates were protected despite initial peripheral autoimmune responses to MOG. In vitro analyses revealed equivalent potentials of fluid phase phagocytosis of myelin and MOG in bone-marrow macrophages derived from both FcRγ+/+ and FcRγ-/- mice, while MOG-immunoglobulin (Ig)G immune complexes were only internalized by FcRγ+/+ macrophages. This was associated with cellular activation in FcRγ+/+ but not FcRγ-/- macrophages, as assessed by the activation of intracellular mitogen activated protein (MAP)-kinase signalling elements. We propose that protection from EAE in FcRγ-deficient mice is due to the inefficient antigen processing/presentation of myelin proteins during the induction of secondary immune responses locally in the CNS, which leads to demyelination. This demonstrates the importance of FcR in the promotion of autoimmune inflammation of the CNS and highlights the therapeutic possibility of treatment of MS with FcR-directed modalities. [ABSTRACT FROM AUTHOR]

Abstract. Johansson Å, Boman K, Cederquist K, Forsberg H, Olsson T (Umeå University Hospital, Umeå, Skellefteå County Hospital, Skellefteå, and Boden Hospital, Boden, Sweden). Increased levels of tPA antigen and tPA/PAI-1 complex in myotonic dystrophy. J Intern Med 2001; 249: 503–510. Objective. To assess the fibrinolytic system in myotonic dystrophy (DM1), a disease connected to features of the metabolic syndrome, including a prominent insulin resistance, increased body fat mass, and hypertriglyceridaemia. We hypothesized that abnormalities in the fibrinolytic system are linked to metabolic dysfunction in DM1. Design. Circulating morning levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) antigens, tPA/PAI-1 complex, lipids and insulin were determined. Genetic analyses, including calculation of allele size, were performed in all patients. Body fat mass was estimated with bioelectrical impedance analysis. Setting. Out-patient clinic in collaboration with Umeå University Hospital. Subjects. A total of 42 otherwise healthy patients with DM1 (22 men, 20 women; median age 41.5 years) and 50 controls (27 men, 23 women; median age 42.0 years). Main outcome measures. The tPA and PAI-1 antigens, tPA/PAI-1 complex, blood lipids and body fat mass. Results. The tPA antigen and tPA/PAI-1 complex levels were significantly increased in DM1 patients (P < 0.001 and P < 0.05, respectively) whilst levels of PAI-1 did not differ from controls. Triglyceride levels were increased (P < 0.001) whereas HDL cholesterol levels were lower in DM1 patients (P < 0.05). Body fat mass was increased in DM1 patients (P < 0.001). Conclusions. The fibrinolytic system is disturbed in DM1 patients, with increased levels of tPA and tPA/PAI-1 complex but paradoxically unaltered levels of PAI-1, in spite of a severely increased body fat mass. This may imply an abnormal function of adipose tissue in DM1, and calls for further studies of the fibrinolytic system in this disease. [ABSTRACT FROM AUTHOR]

Objectives: To compare serum leptin between nonwesternized and westernized populations.Setting: (i) The tropical island of Kitava, Trobriand Islands, Papua New Guinea and (ii) the Northern Sweden MONICA study population. Design. Cross-sectional survey.Methods: Fasting levels of serum leptin were analysed in 163 randomly selected Kitavans aged 20-86 years and in 224 Swedes aged 25-74.Main Outcome Measure: Mean and determinants of serum leptin.Results: Geometric mean of serum leptin in Kitavan males and females were 1.5 and 4.0 vs. 4.9 and 13.8 ng mL-1 in Swedish male and females (P < 0.0001 for both sexes). In Kitavans, observed geometric mean were close to predicted levels (1.8 ng mL(-1) for males and 4.5 ng mL-1 for females) based on multiple linear regression equations including body mass index (BMI), triceps skinfolds (TSF) and age from the Swedish population-based sample. In Kitavans serum leptin was positively related to TSF amongst both sexes and, amongst females, to BMI. In Kitavans leptin was not related to fasting serum insulin. TSF explained 55% of the variation of leptin amongst females. There was a slight age-related increase of leptin amongst males. In Kitava leptin was not related to fasting serum insulin which was substantially lower than in Sweden.Conclusion: The low concentrations of serum leptin amongst Kitavans probably relates to the absence of overweight and hyperinsulinaemia. At a population level serum leptin can apparently be predicted from simple measures of adiposity. [ABSTRACT FROM AUTHOR]

Little is known about solubility and soil solution concentrations of most elements occurring in the solid phase of soils. This study reports changes in solution concentrations of 60 mineral elements following CaCO3 addition to a moderately acid semi-natural soil, and possible mechanisms accounting for the differing solubility patterns as related to soil acidity are discussed. Soil solutions were obtained by high-speed centrifuging and ultrafiltration (0.2 μm) of samples at 60% water-holding capacity of the A horizon of a Cambisol developed from a shale–gneiss moraine and supplied with CaCO3 at 20 rates to yield a soil solution pH range of 5.2–7.8. Concentrations of elements were determined in the solutions by ICP-AES or (for most elements) ICP-MS. Several distinct patterns of soil solution concentrations as a function of soil solution pH were demonstrated. Positively related to pH and CaCO3 supply were soil solution concentrations of As, Br, Mo, S, Sb, Se, U, and W, and to a lesser degree, Co, Cr, Hg, Mg, and Sr. Inversely related to pH were concentrations of Al, B, Ba, Bi, Cs, Ce, Eu, Ga, Ge, Fe, Li, K, Rb, Na, Th, and Ti; less distinctly inversely rated were Dy, Er, Gd, Hf, La, Lu, Mn, Nd, Pr, Sm, Sc, Si, Tl, Tm, and Yb. ‘U-shaped’ relationships to pH were demonstrated for the concentrations of Ag, Cd, Nb, Ni, P, V, and Zr. There were no or irregular relations between pH and concentrations of Be, Cu, Ho, Pb, Ta, and Tb. Differences between elements in their soil solution concentrations as related to total (HNO3-digestible) concentrations and the solubility of organic C were also treated. Increasing the pH of a soil by adding CaCO3 changes the solubility of most mineral elements substantially, the several distinct patterns observed being governed by, for example, ionic properties and charge, affinity for organic compounds, and pH-dependent formation and solubility of complexes. [ABSTRACT FROM AUTHOR]

Abstract. Johansson Å, Ahrén B, Näsman B, Carlström K, Olsson T (Umeå University Hospital, Umeå; Malmö University Hospital, Malmö; Karolinska Instituitet, Huddinge University Hospital, Huddinge, Sweden). Cortisol axis abnormalities early after stroke – relationships to cytokines and leptin. J Intern Med 2000; 247: 179–187. Objective. To assess the relationships between circulating levels of proinflammatory cytokines and adrenocortical hormones and leptin early after stroke. Design. Blood samples were collected four times daily the first two days after stroke, twice daily the next 4 days and four times at day 7. Cognitive function and functional outcome was measured at admittance and at day 7. Setting. Consecutive inclusion of patients admitted to the stroke unit at Umeå University Hospital. Subjects. Eight men and 4 women with acute stroke and 10 healthy volunteers. Main outcome measures. Levels and diurnal variations of plasma proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), serum adrenocortical hormones (cortisol and DHEA) and leptin, and MMSE, SSS, and ADL scores. Results. A significant correlation was present between IL-6 and cortisol levels the first two days after stroke (P < 0.05). In patients with a disturbed diurnal rhythm of cortisol, cortisol and leptin levels were increased (68% and 81% increase, respectively), whilst DHEA levels were unaltered. Half of the patients displayed an abnormal diurnal rhythmicity of leptin at the end of the week. Median TNF-α levels for the first two days after stroke also correlated to median leptin levels at the end of the week (P < 0.05). Median IL-6 levels correlated to severity of paresis on days 1 and 7 and to MMSE scores on day 7 (P < 0.05). Conclusions. Neuroendocrine disturbances are common and often profound early after stroke. Cytokines seem to be important modulators of these disturbances, including diurnal rhythmicity of cortisol and leptin. [ABSTRACT FROM AUTHOR]

Abstract. Walker BR, Soderberg S, Lindahl B, Olsson T (University of Edinburgh, Western General Hospital, Edinburgh, UK and the University of Umea, University Hospital, Umea, Sweden). Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women. J Intern Med 2000; 247: 198–204. Objectives. Recent data suggest that higher plasma cortisol may be associated with hypertension and insulin resistance in otherwise healthy men, as it is in Cushing’s syndrome. However, obesity in women is associated with lower plasma cortisol concentrations. This study sought to establish whether plasma cortisol is associated with cardiovascular risk factors in women as it is in men, and whether these relationships in either sex are confounded by obesity. Design. A population-based cross-sectional study. Setting. The MONICA study in northern Sweden. Subjects. From a target cohort of 2500, 1921 subjects took part and 226 were randomly selected because they attended between 07.00 and 09.00 h after an overnight fast. A 75 g oral glucose tolerance test was performed and blood sampled at baseline and 2 h after glucose. Results. Plasma cortisol was lower in relatively obese subjects: in men, this was observed only in the 2 h sample (r = –0.23, P = 0.02) and in women only in the fasting sample (r = –0.26, P < 0.01). Simple regression analysis did not identify relationships between plasma cortisol and blood pressure, serum lipids, fasting insulin or glucose tolerance. However, after adjusting for the effect of obesity by multiple regression, higher plasma cortisol was independently associated with higher diastolic blood pressure in men (r = 0.21, P = 0.04) but not in women, and higher fasting serum triglyceride levels in women (r = 0.28, P < 0.001) but not in men. Conclusions. Increasing obesity and plasma cortisol concentrations make independent and sex-specific contributions to variations in blood pressure and aspects of the insulin resistance syndrome. Adverse cardiovascular risk is greatest in those with the combination of obesity and failure to downregulate plasma cortisol levels. [ABSTRACT FROM AUTHOR]

Activated, cytokine-producing lymphocytes may regulate central nervous system (CNS) inflammation in multiple sclerosis (MS). We utilize a novel combination of in situ hybridization (ISH) and immunocytochemical staining of peripheral blood lymphocytes (PBLs) to identify spontaneously interferon-gamma (IFNγ) mRNA expressing cells as CD4+ or CD8+. A major proportion of the IFNγ mRNA expressing lymphocytes belonged to the CD4+ lineage, which concords with the cellular composition of MS brain lesions, findings in experimental models and the HLA class II haplotype association in MS. There were also significantly more CD8+ IFNγ mRNA expressing lymphocytes in the MS patients compared with healthy controls, further suggesting the contribution of activated cells from this lineage in the inflammatory response in MS. Both CD4+ and CD8+ IFNγ mRNA expressing cells were enriched in the cerebrospinal fluid (CSF) as compared with the peripheral blood of the MS patients. Combined with emerging genetic data on HLA class I influences, our data argues for a joint role of activated CD8+ and CD4+ cells in the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Background: Leptin is a crucial mediator of satiety signals and energy balance, and its circulating levels are increased in obesity. It has recently been shown that plasma leptin levels in humans correlate with circulating insulin and to insulin secretion. This indicates that leptin may be an important link in metabolic consequences of the insulin resistance syndrome. Whether this includes abnormalities in fibrinolysis has not been studied.Methods and Results: Healthy subjects (n = 165; 85 men and 80 women) from the Northern Sweden MONICA population were investigated. Anthropometric measurements, oral glucose tolerance tests and sampling for plasma leptin, lipids, fibrinogen and fibrinolytic variables were made. Leptin levels were 342% higher in women than in men and were in both sexes strongly correlated to body mass index (BMI). After adjustments for age and BMI, leptin levels correlated significantly to pre/post glucoseload insulin levels in both sexes. After further adjustment for baseline insulin levels, leptin levels were in males significantly associated with increased waist circumference (P<0.001), low HDL cholesterol (P<0.05), low tPA activity (P<0.01) and high PAI-1 activity (P<0.001). In postmenopausal females, a significant association between leptin and low tPA activity/high PAI-1 activity was seen after adjustment for age and BMI (P<0.05). Conclusions. Circulating levels of leptin are associated with components of the insulin resistance syndrome, including defective fibrinolysis, in men and postmenopausal women. This suggests that leptin may be involved in the mediation of consequences of insulin resistance. [ABSTRACT FROM AUTHOR]