Biomedical subjects

S Fredrikson

Publications and source records attributed to S Fredrikson.

At least 37 records · Page 2Linked to original sources

PubMed2000

Linkage analysis of a candidate region in Scandinavian sib pairs with multiple sclerosis reveals linkage to chromosome 17q.

To date, four genome screens have been completed in the demyelinating autoimmune disease multiple sclerosis (MS). Although these screens failed to identify any loci with major effects on susceptibility, several novel regions of potential linkage were suggested, including the long arm of chromosome 17. In order to further pursue this promising region we have investigated six highly polymorphic microsatellite markers in 115 Scandinavian families with MS affected sib pairs. Multipoint linkage analysis revealed a peak maximum likelihood score (MLS) of 0.9 in the region of marker D17S787. Stratifying the results on the basis of HLA-DR2 status showed that the linkage was not limited to families segregating for the HLA-DR2 allele as has previously been suggested. In conclusion, our results further support the proposal that a multiple sclerosis susceptibility locus is contained on chromosome 17q.

Chromosomes, Human, Pair 17↗

PubMed2000

Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis.

Interferon-beta (IFN-beta) is currently the most commonly used treatment of relapsing-remitting multiple sclerosis (MS). At the time of this study, two preparations of IFN-beta were available, IFN-beta-1a (Avonextrade mark) and IFN-beta-1b (Betaferon(R)), which both can elicit an immune response with the development of anti-IFN-beta antibodies. Direct comparisons between these two preparations regarding antibody frequencies have, however, been difficult to perform, because two different analysis methods measuring partly different biological effects of IFN-beta have been employed. In the present study, binding and neutralizing anti-IFN-beta-1a and -1b antibodies were detected in parallel by an independent, well-acknowledged, interferon research laboratory using an immunoassay and a cytopathic virus inhibition assay. Five per cent of patients treated with IFN-beta-1a intramuscularly (n = 20) had neutralizing antibodies (NABs) compared with 44% of patients treated with IFN-beta-1b subcutaneously (n = 48). A high degree of cross-reactivity between neutralizing anti-IFN-beta-1a and -1b antibodies was observed. No effect of NABs on clinical outcome could be detected in this limited material. Binding anti-IFN-beta antibodies were observed in 20% of IFN-beta-1a treated patients compared with 81% of patients treated with IFN-beta-1b. Only one of 17 patients examined (6%) had detectable titres of binding anti-IFN-beta-1b antibodies in the cerebrospinal fluid (CSF). These data are the first using identical methodology to show that IFN-beta-1a gives rise to fewer NABs than IFN-beta-1b at recommended treatment schedules.

Adjuvants, Immunologic↗

PubMed2000

Decreased mRNA expression of TNF-alpha and IL-10 in non-stimulated peripheral blood mononuclear cells in myasthenia gravis.

Myasthenia gravis (MG) is characterized by T cell-dependent autoantibodies to the acetylcholine receptor on the post-synaptic membrane of the neuromuscular junction. The production of autoantibodies is regulated by T cells via cytokines. To investigate the involvement of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4) and interleukin-10 (IL-10) in MG, the mRNA levels of these cytokines in peripheral blood mononuclear cells without stimulation in vitro were quantified by competitive reverse transcription polymerase chain reaction technique. The mRNA level of TNF-alpha was significantly lower (P = 0.0004) in the overall group of MG patients compared with controls. IL-10 was also lower in MG patients (P = 0.008), most markedly in non-thymectomized patients (P = 0.016). There were no significant differences in IFN-gamma and IL-4 between patients and healthy controls, but the mRNA levels of IL-4 in non-thymectomized patients was significantly lower than in controls (P = 0.02) and in thymectomized patients (P = 0.03). These results, reflecting the in vivo expression pattern of these cytokines in the periphery, suggest an altered cytokine expression at the systemic level in MG.

Adult↗

PubMed2000

Clinical epidemiology of Guillain-Barré syndrome in adults in Sweden 1996-97: a prospective study.

We described clinical manifestations, outcomes, prognostic indicators and clinico-epidemiological subgroups for 53 adult patients with Guillain-Barré syndrome (GBS) in Sweden during the period 1996-97. These patients were identified from a population of 2.8 million inhabitants and prospectively followed up for one year by a network of neurologists. An additional 10 cases, of whom five were adults who had not been prospectively followed up, were not included in the analyses. At 6 months after onset 80% of the patients could walk without aid, while at 1 year 46% were fully recovered, 42% had mild residual signs or symptoms, 4% had moderate and 6% severe disabilities, and 2% had died. Intravenous human immunoglobulin or plasmapheresis were used in 72% of the patients. The sum of the Medical Research Council (MRC) score at nadir was found as the only significant predictor for residual signs at 1 year in a multivariate model. Three subgroups, with different clinico-epidemiological characteristics, were identified by using cluster analysis. In conclusion, GBS in Sweden is frequently preceded by a respiratory infection, is often treated with immunomodulatory therapies, and exhibits a high recovery rate and a low fatality rate.

Adult↗

PubMed2000

Interferon-beta treatment for patients with multiple sclerosis: the patients' perceptions of the side-effects.

The aims of this study were to investigate (i) the self-reported frequency and intensity of systemic side-effects and their impact on the daily lives of patients suffering from Multiple Sclerosis (MS) and undergoing interferon-beta therapy and (ii) the self-reported frequency and perceptions of any local-tissue reactions. Forty patients aged 22 - 59 years (27 females) with relapsing/remitting MS were consecutively recruited for the study (17 on interferon-beta-1a and 23 on interferon-beta-1b). Two self-administered questionnaires were used before and after 1, 4, 8 and 16 weeks of therapy. The interferon therapy was found to be associated with flu-like symptoms. Most systemic side-effects were reported to be mild and to have little impact on the patients' daily lives. Asthenia and fatigue were more often rated as moderate or severe. The most frequently reported local-tissue side-effects were redness and local pain at the injection sites. A considerable inter-individual variation was found among patients regarding the perceptions of both the systemic and local side-effects. This suggests that it is of importance to identify early those patients who may need more support or other interventions to maintain a successful compliance. Multiple Sclerosis (2000) 6 349 - 354

Activities of Daily Living↗

PubMed2000

Incidence of Guillain-Barré syndrome in Sweden 1996.

We describe the incidence of Guillain-Barré syndrome (GBS) in Sweden in 1996. Information of incident GBS patients was mainly collected by a multicentre network of 18 neurologists prospectively monitoring a general population with 4.48 million inhabitants across the country and complemented with data from the national hospital in-patient registry. GBS diagnoses for all patients were validated by neurologists. While 53 patients with GBS were identified by the network neurologists from the study population, the other 20 GBS patients were recognized after carefully reviewing the registered data. There were 44 (60%) male patients and 29 (40%) female patients and the mean age at onset for all patients was 48.6 (SD 24.3) years. The GBS incidence, age-adjusted to the European standard population, was 1.51 (95% CI 1.18-1.90) per 100 000 person-years in 1996, higher in males and increased with age. When compared with selected studies, the GBS incidence in Sweden is moderately high, and the variation of GBS incidence in Europe seems to be small.

Adolescent↗

PubMed1999

[Place of residence determines access to interferon-beta therapy in MS. Less than 15 per cent of patients are treated--big differences between the counties].

Interferon-beta (IFNB) is the first agent to be registered in Sweden for modifying disease course in multiple sclerosis (MS). A nationwide survey uncovered a tenfold variation between counties in the prescribing of IFNB. About 10% of patients received treatment in a few counties, while in most the figure was even smaller. No correlation was found between sales of IFNB and numbers of neurologists in the respective counties. Patients should receive treatment according to national medical guidelines, regardless of place of residence.

Drug Costs↗

PubMed1999

Multiple sclerosis is associated with high levels of circulating dendritic cells secreting pro-inflammatory cytokines.

Recent evidence emphasises a pivotal role for dendritic cells (DC) in the control of immunity by priming and tolerising T cells. DC capture and process antigens, express co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. In multiple sclerosis (MS), autoreactive T cells are proposed to play a pathogenic role by secreting pro-inflammatory cytokines, but studies on DC are lacking. To evaluate the involvement of DC in patients with MS, a modified procedure was used to prepare DC from blood of patients with MS and healthy subjects. DC were found to be potent stimulators of T cells in allogeneic and, to a lesser extent, in autologous mixed leukocyte reaction (MLR). Enzyme-linked immunospot (ELISPOT) assays were adopted to determine levels of IFN-gamma, TNF-alpha, IL-6 and IL-10 secreting DC vs. mononuclear cells (MNC). Proportionally more DC than MNC secreted IFN-gamma and IL-10 in both MS and healthy subjects. Patients with MS had higher levels of IFN-gamma, TNF-alpha and IL-6 secreting DC than healthy subjects. The differences for IFN-gamma and TNF-alpha secreting cells were confined to the subgroup of untreated MS patients and not observed in the subgroup examined during ongoing treatment with IFN-beta. Circulating DC secreting pro-inflammatory cytokines may represent another focus for the study of both immuno-pathogenesis and therapeutic interventions in MS.

Adult↗

PubMed1999

Bilateral subdural haematomas following lumbar puncture in three haematopoietic stem cell transplant recipients.

Between 1990 and 1996, three patients (1.1%), all with CML, among 272 patients with haematological malignancies, developed bilateral subdural haematomas (SDH) after treatment with i.t. MTX before HSCT in our unit. Since October 1996, we have given i.t. MTX only to patients at increased risk of CNS leukaemia such as ALL and AML M4 or M5. We suggest that intrathecal treatment before HSCT should only be given to patients at increased risk of CNS leukaemia.

Adult↗

PubMed1999

Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment.

The cytokine interleukin (IL)-10 has immune response down-regulatory properties, which include suppression of the synthesis of pro-inflammatory cytokines such as interferon (IFN)-gamma and of major histocompatibility complex (MHC) class II expression on monocytes. To further elucidate the involvement of IL-10 in multiple sclerosis (MS), an enzyme-linked immunospot assay was adopted to enumerate IL-10-secreting mononuclear cells (MNC) in peripheral blood. IFN-gamma secreting MNC were detected in parallel. Levels of IL-10-secreting cells were lower in patients with MS compared with other neurological diseases (OND) and healthy subjects. This difference was seen only in patients with untreated MS, and not in those undergoing treatment with IFN-beta-1b. No differences were observed when subgrouping the patients with MS regarding clinical phase (exacerbation, remission, secondary progression), duration of MS or disability status. Levels of IFN-gamma-secreting blood MNC did not differ in patients with MS, irrespective of treatment with IFN-beta-1b, compared with OND and healthy subjects. Patients with MS, but not the two groups of controls, had elevated numbers of IL-10- and IFN-gamma-secreting cells upon stimulation with MBP compared with culture in the absence of antigen. The data suggest that IL-10 is decreased in MS and that treatment resulting in its up-regulation beneficially influence the disease.

Adult↗

PubMed1999

High numbers of perforin mRNA expressing CSF cells in multiple sclerosis patients with gadolinium-enhancing brain MRI lesions.

Enhanced expression of pro- and anti-inflammatory cytokines is a common finding in MS, but attempts to correlate cytokine expression with disease activity have produced conflicting results. In this paper, gadolinium-(Gd-)enhancing lesions on brain MRI were used as markers for active inflammation in patients with MS not treated with any immunomodulatory drugs. In parallel, in situ hybridization was used to detect blood and cerebrospinal fluid (CSF) mononuclear cells (MNC) expressing cytokine mRNA. An association was observed between numbers of perforin mRNA expressing CSF MNC and numbers of Gd-enhancing brain MRI lesions. Perforin mRNA expressing CSF MNC were not detected in any of the patients lacking active lesions on brain MRI. The expression of tumor necrosis factor-alpha, interleukin-10 (IL-10) and IL-12 mRNA in CSF MNC did not differ between MS patients with and without active MRI lesions. Based on the present finding, a role for perforin in the disruption of the blood-brain barrier in MS can be hypothesized.

Adult↗

PubMed1999

First hospital-admission rate as an epidemiological indicator for patients with multiple sclerosis in Stockholm, 1984-1993.

OBJECTIVES: To evaluate the first hospital-admission patients with multiple sclerosis (MS) in the population. MATERIAL AND METHODS: By using the data from hospital discharge registry of MS diagnosis in Stockholm during 1984-1993, we calculated rates of first hospital-admission patients with MS in the population and evaluated the temporal trend of the rates during the study period. RESULTS: There were 719 first hospital-admission patients with MS corresponding to 1556 admissions. The mean age at the first admission was nearly the same for male patients (44.3 years, SD: 12.9) and for female patients (44.6 years, SD: 13.7). The mean annual rate of first hospital-admission patients with MS was 4.46 per 100,000 person-years. The sex rate ratio of first hospital-admission patients with MS between females and males was 2.19:1. CONCLUSION: The first hospital-admission rate of MS could be used as an epidemiological indicator which is useful in planning of hospital service for MS patients.

Adolescent↗

PubMed1999

A new cell enzyme-linked immunosorbent assay demonstrates gamma interferon suppression by beta interferon in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system of unknown etiology. Immune mechanisms involving the proinflammatory cytokine gamma interferon (IFN-gamma) are believed to play an important role in the pathogenesis of MS. IFN-beta-1b has been introduced as a treatment for MS and was found to reduce the number and severity of clinical exacerbations. To examine the influence of IFN-beta-1b on myelin basic protein (MBP)-specific and phytohemagglutinin-induced IFN-gamma production, we developed a cell-released capturing enzyme-linked immunosorbent assay (CRC-ELISA), which rapidly measures spontaneous and antigen- or mitogen-induced cellular IFN-gamma production. CRC-ELISA documented a significant MBP-specific T-cell response in the blood of untreated MS patients, as assessed by IFN-gamma production. This response was suppressed in MS patients treated with IFN-beta-1b. The present work confirms in vivo the in vitro suppressive effects of IFN-beta-1b on IFN-gamma production in MS. Moreover, it provides a powerful new technique for detection of cytokines.

Adult↗

PubMed1999

Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls.

Several studies have suggested an association between human herpesvirus 6 (HHV-6) and multiple sclerosis (MS). We have previously studied intrathecal production of antibody to lymphotropic herpesviruses in MS patients and the presence of human herpesvirus 1 to 7 DNAs in cerebrospinal fluid (CSF). In the present study anti-HHV-6 immunoglobulin M (IgM) in serum and anti-HHV-6 IgG subclasses in serum and CSF were examined and the lymphoproliferative response to HHV-6 was analyzed. The PCR examination was refined by purifying DNA from CSF and retesting the samples for HHV-6 DNA. There were no statistically significant differences between the groups concerning IgM positivity, distribution of IgG subclasses, or lymphoproliferative response to HHV-6. The purification of DNA increased the number of PCR-positive samples from 0 of 71 to 4 of 68. The study does not give additional support to the possibility that HHV-6 is a common cause of MS, but a role for the virus in a subset of patients cannot be excluded.

Adolescent↗

PubMed1999

Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.

Myelin-directed autoimmunity is considered to play a key role in the pathogenesis of multiple sclerosis (MS). Increased production of both pro- and anti-inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively by activated memory T cells, which can induce the production of proinflammatory cytokines and chemokines from parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM) compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected in MS patients examined during clinical exacerbation compared to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrate increased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, and with the highest numbers in blood during clinical exacerbations.

Adult↗

PubMed1999

Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis.

In the genetically homogeneous Scandinavian population, we have investigated chromosome 5 and the HLA (human leukocyte antigen) region on chromosome 6p21 by applying linkage and association analyses on 106 white sibling pair families with multiple sclerosis. The importance of genes within the HLA region for the susceptibility of multiple sclerosis has previously been reported. More recently, findings have suggested importance of regions on chromosome 5. Half of chromosome 5 was analyzed by using 14 microsatellite markers and a susceptibility region with a maximum LOD score of 1.1 was identified. Chromosome 6 was analyzed by HLA-DR typing and using the TNF alpha microsatellite marker. A peak maximum LOD score of 2.0 was found at the HLA-DR marker. Association studies were made for all the markers, comparing 106 probands from the sibling pairs with 100 unrelated controls. None of the markers on chromosome 5 showed significant association with multiple sclerosis, whereas strong association between multiple sclerosis and DR2 was found, with an odds ratio of 3.7 (p < 10(-5)). It is surprising that association was not seen for any of the TNF alpha alleles including the 121-bp allele, although this allele was in positive linkage disequilibrium with DR2 in both patients and controls. Our results support the existence of multiple sclerosis susceptibility loci on chromosomes 5p and 6p21.

Chromosome Mapping↗

PubMed1998

No evidence for elevated numbers of mononuclear cells expressing MCP-1 and RANTES mRNA in blood and CSF in multiple sclerosis.

The perivascular accumulation of mononuclear cells (MNC) in brain white matter is critical in the development of active lesions in multiple sclerosis (MS). Chemokines contribute to leukocyte recruitment by increasing the adhesiveness of integrins expressed on leukocytes and by promoting migration through endothelium and extracellular matrix. By using an in situ hybridization technique, it was possible to enumerate blood and CSF MNC expressing mRNA for the two CC chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES (regulated upon activation, normal T cells, expressed and secreted) in MS patients and controls. No differences in numbers of blood MNC expressing MCP-1 or RANTES could be found in MS patients compared to healthy individuals or patients with acute aseptic meningoencephalitis (AM). High numbers of CSF MNC expressing MCP-1 and RANTES were found in some MS patients, but also in patients with AM. This shows that elevated numbers of MCP-1 and RANTES mRNA expressing CSF MNC are not specific for the inflammatory process in MS. We conclude that there is no evidence for a systemic dysregulation of the CC chemokines MCP-1 and RANTES in MS.

Adult↗

PubMed1998

Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis.

Several genetic factors are likely to play a role in the etiology of multiple sclerosis (MS). We used a candidate gene strategy in a study of polymorphic markers within or close to genes encoding cytokines (interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-4 receptor (IL-4R), IL-10, transforming growth factor-beta1 and -beta2) and myelin proteins (2',3'-cyclic-nucleotide 3'-phosphohydrolase (CNP:ase), myelin associated glycoprotein, oligodendrocyte myelin glycoprotein, proteolipid protein) in 34 Swedish multiplex MS families and in 147 sporadic MS patients and 95 healthy controls. No evidence for linkage was observed in two-point linkage analysis. However, a slightly positive LOD score of 0.88 (theta = 0.01) for IFN-gamma was found. Affected pedigree member (APM) analysis indicated a possible linkage with TGF-beta2 (p = 0.008) and IL-4R (p = 0.043). None of the cytokine markers were associated with MS in case-control analysis. Our results suggest a possible importance of the TGF-beta2, IL-4R and IFN-gamma genes in MS.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗