Biomedical subjects

T Olsson

Publications and source records attributed to T Olsson.

At least 73 records · Page 4Linked to original sources

PubMed2000

PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia.

Using genome screen, DNA sequence and mapping data, we scanned the human chromosomal region 17q21-q24 for polymorphic markers in single copy genes. Three such genes were identified: the gene for myeloperoxidase (MPO) at 17q21.3-q23.2, containing a CA-microsatellite in the eighth intron and a functional single base substitution (G to A) in the promoter region, the platelet endothelial cell adhesion molecule-1 gene (PECAM1) at 17q23, which has a CA-repeat sequence in the sixth intron, and the gene for the regulatory subunit RIalpha of cAMP-dependent protein kinase (PRKAR1A) at 17q23-q24, in which a GA-microsatellite was detected in the 5'-flanking region. Association of these polymorphisms with multiple sclerosis (MS) was studied in a Swedish case-control population of 199 MS patients and 145 control subjects, and in 203 simplex families from Sardinia. None of these polymorphic genes was found to be a genetic marker for disease susceptibility. These results are in contrast with previous studies on the involvement of MPO in MS and suggest that the elevated expression of PECAM-1 in MS, as earlier documented, is related to transactivation by other gene products.

Adult↗

PubMed2000

Rigid fusion after cloward operation for cervical disc disease using autograft, allograft, or xenograft: a randomized study with radiostereometric and clinical follow-up assessment.

STUDY DESIGN: In this study, 43 patients scheduled for a single-level cervical Cloward procedure for disc disease were randomized prospectively to fusion with autograft, allograft, or xenograft. OBJECTIVE: To outline any differences in fusion over time in terms of final mobility and clinical outcome between the three bone grafts. SUMMARY OF BACKGROUND DATA: Fusion is used to relieve pain from a spinal segment. The bovine xenograft gives a fibrous fusion in contrast to the solid bone fusion obtained with autograft from the iliac crest, but no definite differences in clinical outcome have been shown previously after surgery at a single level. METHODS: By use of radiostereometric analysis, 33 patients were observed after 6, 12, and 24 to 50 (mean, 37) months. All 43 patients underwent clinical examination, which involved pain rating before and after surgery, with a final follow-up assessment by an unbiased observer. RESULTS: Mobility could be demonstrated in 9 patients after 1 year and in 6 patients at the final follow-up assessment, without pain, and with no difference between bone grafts. The patients who received autograft experienced a greater reduction of pain than the patients treated with xenograft. CONCLUSIONS: Most of the patients healed with a rigid fusion no matter which graft was used, but the healing process took longer than expected. The clinical results were not influenced by whether mobility could be demonstrated. There was a tendency toward better clinical results in the patients treated with autograft.

Animals↗

PubMed2000

Genetics of rat neuroinflammation.

The definition of genes regulating the pathogenetic pathways of autoimmune neuroinflammation, may provide targets for new therapeutic strategies. This is not easily accomplished in human disease. Such genetic dissection can more readily be done by the use of inbred rodent strains. With these, genetic heterogeneity is avoided and variation in the environmental influences is minimized. Close mimicking of the human disease characteristics is desirable in such endeavors. Chronic relapsing experimental autoimmune encephalomyelitis (EAE) with MS-like histopathology is achieved after immunization of certain rat strains with myelin oligodendrocyte glycoprotein (MOG) or spinal cord homogenate. The major histocompatibility complex (MHC) regulate the ease by which the environmental trigger in the form of immunisation induces disease. Use of intra-MHC recombinant strains demonstrated major influences from the MHC class II genome region, but additional influences from both the MHC class I and III regions. These findings now provide a basis for studies of the mechanisms for MHC-controlled autoimmune pathogenicity leading to MS-like disease. Gene mapping of F2 crosses between susceptible and resistant rat strains demonstrated nine genome regions outside the MHC which regulate different phenotypes of rat EAE. Many of these co-localize with genome regions regulating other organ-specific disease such experimental arthritis, suggesting a sharing of disease pathways. Further finemapping can lead to the exact identification of disease regulating genes. Interestingly, we have also demonstrated a non-MHC gene control of the inflammatory response, in the form of glial cell activation, and neuronal degeneration, subsequent to anterior nerve root avulsion in rats. The genetic dissection of these influences may unravel pathways controlling CNS vulnerability.

Animals↗

PubMed2000

Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells.

In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.

Animals↗

PubMed2000

[Astrocytes--anonymous cells in the brain, participating in neurasthenic symptoms].

During rehabilitation after brain damage due to stroke or trauma, or after meningitis, patients often suffer from mental fatigue and decreased capacity for concentration and learning. We hypothesize that one pathogenic cause of these symptoms could be a failure on the part of astroglia to remove glutamate and K+ from synaptic regions during glutamatergic transmission. As astroglial support of neuronal glutamate transmission has been shown to be of utmost importance, such an astroglial failing might lead to a decreased signal-to-noise ratio in glutamatergic neurotransmission, especially when the transmission is intense for a considerable time period. Three aspects of astroglial failing are focused upon: decreased capacity of the astroglial glutamate transporters, depolarization of the astroglial network, and uncoupling of the gap junction coupled astroglial network. It has been shown that several neuroactive substances, present within the nervous system even long after damage or infection, influence upon these three astroglial properties.

Animals↗

PubMed2000

Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis.

The human gelatinase B (MMP-9) gene promoter region contains a CA microsatellite repeat and a single nucleotide polymorphism which are known to influence transcriptional activity. These two polymorphisms were used to investigate the existence of an association between multiple sclerosis (MS) susceptibility and the MMP-9 gene. In a case-control analysis of 345 Swedish individuals and in a study of 125 Sardinian simplex families no genetic associations between the gelatinase B gene polymorphisms and MS susceptibility were found. These data reinforce the suggestion of epistasis in the regulation of the metalloproteinase-inhibitor balance in MS.

Base Sequence↗

PubMed2000

Reduction of both pro- and anti-inflammatory cytokines after 6 months of interferon beta-1a treatment of multiple sclerosis.

Treatment of multiple sclerosis (MS) with interferon beta (IFNbeta) reduces relapse rate, magnetic resonance imaging (MRI) activity and progression of disability. It has been suggested that this beneficial effect is paralleled by an inhibition of proinflammatory cytokines such as interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) and an induction of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this study, we record a reduced number of spontaneously IFNgamma mRNA-expressing cerebrospinal fluid mononuclear cells (CSF-MC) and IFNgamma, TNFalpha and IL-10 mRNA-expressing peripheral blood mononuclear cells (PBMC) after 6 months of IFNbeta-1a treatment, paralleled by a decreased purified protein derivate (PPD)-stimulated and unstimulated IFNgamma secretion by PBMC. These effects were not apparent after 2 weeks of treatment, and IFNbeta-1a induced IFNgamma production by naive PBMC in vitro. We did not record increased numbers of IL-4 mRNA-expressing CSF-MC or PBMC, increased plasma IL-10 levels, increased numbers of IgG, A or M secreting plasma cells or in vitro induction of IL-10 production by IFNbeta-1a. We conclude that long-term cytokine modulation by IFNbeta-1a differs from acute effects and that downregulation of both pro- and anti-inflammatory cytokines, rather than a shift in the cytokine profile, is apparent after 6 months of IFNbeta-1a treatment of MS patients.

Adjuvants, Immunologic↗

PubMed2000

Protective DNA vaccination against organ-specific autoimmunity is highly specific and discriminates between single amino acid substitutions in the peptide autoantigen.

DNA vaccines that encode encephalitogenic sequences in tandem can protect from subsequent experimental autoimmune encephalomyelitis induced with the corresponding peptide. The mechanism for this protection and, in particular, if it is specific for the amino acid sequence encoding the vaccine are not known. We show here that a single amino acid exchange in position 79 from serine (nonself) to threonine (self) in myelin basic protein peptide MBP68-85, which is a major encephalitogenic determinant for Lewis rats, dramatically alters the protection. Moreover, vaccines encoding the encephalitogenic sequence MBP68-85 do not protect against the second encephalitogenic sequence MBP89-101 in Lewis rats and vice versa. Thus, protective immunity conferred by DNA vaccination exquisitely discriminates between peptide target autoantigens. No bystander suppression was observed. The exact underlying mechanisms remain elusive because no simple correlation between impact on ex vivo responses and protection against disease were noted.

Animals↗

PubMed2000

Peripheral nerve injury induces endoneurial expression of IFN-gamma, IL-10 and TNF-alpha mRNA.

Axotomy of a peripheral nerve leads to interruption of axon continuity with Wallerian degeneration in the distal segment and regenerative events in the proximal remaining neuron. Local inflammation is a consequence of trauma in general and signal molecules regulating inflammation, such as cytokines, participate in the outcome of nerve trauma. We studied a broad set of potent immunoregulatory cytokines after transection of rat sciatic nerve. The endoneurium of the transected rat sciatic nerve was taken from both proximal and distal stumps. The pooled endoneurium of 6 rats was studied using reverse transcription polymerase chain reaction (RT-PCR) after 14 h; 1, 3, 5, 7 days; 2 and 4 weeks after transection. A new observation was that TNF-alpha mRNA showed phasic expression pattern; three distinct peaks were seen, immediately (14 h), after 5 days and in the distal part also after 2 weeks. This phenomenon may be related to the breakdown of the blood-nerve barrier and to the recruitment of circulating macrophages. We further noticed that IFN-gamma mRNA was expressed between 5 days and 2 weeks. This suggests that T-cells may also take part in the regenerative processes. Furthermore, we observed that IL-10 mRNA is expressed continuously during Wallerian degeneration. The continuous expression of IL-10 mRNA may attenuate the production of inflammatory cytokines by macrophages and other cells.

Animals↗

PubMed2000

Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat.

There is a latency period of several weeks before the onset of clinical effect of antidepressant drugs. The detailed mechanisms underlying drug-induced adaptive neuronal changes are not known. To elucidate the involvement of changes in gene expression of candidate transcription factors, we treated rats for 21 days with buspirone, fluoxetine, 8-OH-DPAT and moclobemide. In situ hybridization was used to study mRNAs encoding NGFI-A, NGFI-B and the glucocorticoid receptors, MR and GR. NGFI-A mRNA expression increased profoundly in the hippocampal formation and the cerebral cortex after all drug treatments, especially after moclobemide treatment (77-122% increase); with the exception of buspirone. MR mRNA expression was induced in hippocampal CA1/CA2 subregions (27-37%) by all antidepressants, while moclobemide and 8-OH-DPAT significantly increased GR gene expression mainly in the CA1 region (31-44%). NGFI-B mRNA was significantly decreased in the hippocampal CA3 subfield (23%) and restrosplenial granular cortex (38%) by moclobemide treatment. There are selective effects of antidepressant drugs on specific transcription factors. These may be important for adaptive neuronal and neuroendocrine changes after antidepressant treatment including HPA axis negative feedback regulation.

Animals↗

PubMed2000

Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions.

Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.

Acute Disease↗

PubMed2000

Lack of association between the interferon regulatory factor-1 (IRF1) locus at 5q31.1 and multiple sclerosis in Germany, northern Italy, Sardinia and Sweden.

Interferon regulatory factor-1 (IRF-1) is a transcriptional inducer of the interferon-beta (IFN-beta) gene and other interferon-stimulated genes. A GT repeat polymorphism in the 7th intron of the IRF-1 gene was used as a marker to test for association with multiple sclerosis (MS) in a case-control study including individuals from Germany, Northern Italy and Sweden. In none of these populations, did we find any significant allelic association with disease. This lack of association was confirmed by testing transmission disequilibrium of individual IRF1 alleles in a representative sample of Sardinian simplex MS families. No deviation of the expected 50% transmission rates was seen. Therefore, our work does not provide evidence in favor of IRF1 being a candidate for conferring genetic susceptibility to, or protection against, MS in Europe.

Adolescent↗

PubMed2000

Cortisol axis abnormalities early after stroke--relationships to cytokines and leptin.

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 Umeâ 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-alpha (TNF-alpha), 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-alpha 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.

Adrenocorticotropic Hormone↗

PubMed2000

Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women.

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.

Aged↗

PubMed2000

Early and delayed induction of immediate early gene expression in a novel focal cerebral ischemia model in the rat.

This study aimed at evaluating changes in expression of immediate early genes in a new photothrombotic focal ischemia model that exhibits late spontaneous reperfusion and morphological restoration in the region-at-risk within the cerebral cortex. Gene expression was studied with Northern blots, in situ hybridization and immunohistochemistry. At early time points (1-4 h), nerve growth factor-induced gene A and B, and c-fos mRNAs, were quickly induced throughout the ipsilateral cortex, with no obvious differences between the region-at-risk and remote cortical areas. High concentrations of nerve growth factor-induced gene A and c-Fos proteins were present within the region-at-risk even when cortical cerebral blood flow was as low as 40% of control values. At 4 h the nerve growth factor-induced gene A mRNA and protein expression was significantly decreased in the hippocampus vs. naive controls. However, a small decrease was also found in sham-operated and anaesthetized controls. A late induction, at 5 days, of c-fos and nerve growth factor-induced gene B mRNAs was seen bilaterally in the hippocampus and also, in the case of nerve growth factor induced-gene B, in the contralateral cortex. A complex pattern of changes in immediate early gene expression occurs after reversible focal cortical ischemia. This may be important for tissue recovery as well as neuropsychiatric symptoms after stroke.

Animals↗

PubMed2000

Increased numbers of mononuclear cells from blood and CSF expressing interferon-gamma mRNA in multiple sclerosis are from both the CD4+ and the CD8+ subsets.

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 (IFNgamma) mRNA expressing cells as CD4+ or CD8+. A major proportion of the IFNgamma 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+ IFNgamma 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+ IFNgamma 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.

Adult↗

PubMed2000

Genetic regulation of nerve avulsion-induced spinal cord inflammation.

In the animal model for multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), genetic loci correlating with incidence or severity of disease are located both within and outside of the major histocompatibility complex (MHC). Whereas polymorphisms within MHC class I and II molecules are likely to be a major determinant of MHC gene influence in rat EAE, it is still unclear how non-MHC gene regions influence disease. Genetic control of inflammation can hypothetically be either general or specific for a particular target tissue. For the latter, gene regulation of pathomechanisms in the CNS could affect reactivity of microglia or astrocytes, local cytokine/chemokine production, or even neuronal vulnerability. We have obtained strong support for this notion by observations of rat strain-dependent variation in the inflammatory response after ventral root avulsion, a model in which mainly non-antigen-specific elements of the immune system promote inflammation. A comparison of strains with similar MHC haplotypes on different backgrounds and strains with different MHC haplotypes on the same background, respectively, demonstrates that the inflammatory phenotype is regulated mainly by non-MHC genes. Interestingly, different features of the inflammatory response, such as induction of MHC class II expression, glial activation, cytokine expression, and neuronal vulnerability, varied between rat strains and were largely independent of each other. The genetic control of several basic features of inflammation in the CNS is of great relevance not only for MS/EAE, but also for several other neurological conditions with inflammatory components such as cerebrovascular and neurogenerative dieases and trauma.

Animals↗

PubMed2000

Abnormal cytokine and adrenocortical hormone regulation in myotonic dystrophy.

Metabolic-endocrine dysfunctions, including hyperinsulinemia, hypertriglyceridemia, increased fat mass, and dysregulation of the hypothalamic-pituitary-adrenal axis, are common in myotonic dystrophy (MD). We hypothesized that increased production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) may be important underlying mechanisms. We studied the diurnal rhythmicity of cytokines and cortisol, ACTH, and dehydroepiandrosterone in 18 men with adult onset MD and 18 controls. Morning levels of androstenedione, 17-hydroxyprogesterone, testosterone, and insulin were also determined. Genetic analyses were performed, including calculation of allele sizes. Median circulating 24-h levels of IL-6 (P < 0.001), TNF-alpha (P = 0.05), ACTH (P < 0.05), and cortisol (P < 0.05) were all significantly increased in MD, whereas dehydroepiandrosterone levels were decreased (P < 0.001). The diurnal rhythms of these cytokines/ hormones were disturbed in patients. Morning testosterone levels were decreased and insulin levels increased (P < 0.01 for both). Patients with high body fat mass had significantly increased insulin levels and decreased morning levels of cortisol, ACTH, and testosterone. IL-6 and TNF-alpha levels are increased and adrenocortical hormone regulation is disturbed in MD. Adiposity may contribute to these disturbances, which may be of importance for decreased adrenal androgen hormone production and metabolic, muscular, and neuropsychiatric dysfunction in MD.

Adipose Tissue↗