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Biomedical subjects

M Söderström

Publications and source records attributed to M Söderström.

At least 19 recordsLinked to original sources
PubMed2004

Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis.

OBJECTIVES: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis. METHODS: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints. RESULTS: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration. CONCLUSION: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

Animals↗
PubMed2004

Cerebrospinal fluid levels of brain specific proteins in optic neuritis.

This study evaluates levels of cerebrospinal fluid (CSF) brain-specific proteins (BSP) in subjects with optic neuritis (ON) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute ON and 17 subjects with other neurological diseases (OND) served as controls. Twenty-one subjects with ON had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (CDMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfH(SM134) and NfH(SM135)) were analysed using ELISA technique. A putative index of 'axonal health' was expressed as a ratio of NfH(SM134) to NfH(S135). NfH(SM134) and the NfH(SM134:SM135) were significantly elevated in subjects with ON compared to controls. No significant differences in levels of CSF BSP were seen between ON subjects with CDMS plus those at high risk of progression to MS and ON subjects with normal MRI and negative CSF analysis. In conclusion, there is evidence of axonal damage in subjects who present with ON, which is independent of the diagnosis of CDMS.

Adult↗
PubMed2003

Multiple sclerosis: rationale for early treatment.

MS often presents as acute unilateral optic neuritis (ON). While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. As patients become increasingly wellinformed and with the development of effective pharmacotherapy for MS, the distinction between those patients with ON who have MS and those who do not has become ever more important. Recent randomized clinical trials in patients with ON or other clinically isolated syndromes (CIS) suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain found that treatment with recombinant interferon-beta-1a is beneficial in reducing the development of CDMS. Ophthalmologists and other non-neurologists should refer patients with acute ON or other CIS suggestive of MS to a neurologist for MS-directed investigations.

Humans↗
PubMed2003

Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables.

Magnetic resonance imaging (MRI) remains the most valuable tool for monitoring disease activity and progression in patients with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS) with presumably autoimmune etiology. Chemokine receptors have been implicated in MS as key molecules directing inflammatory cells into the CNS. Regulatory (CD4+CD25+) T cells (Tr cells) are important in suppressing autoimmunity, and their absolute or functional deficit could be expected in MS. In the present study, venous blood was obtained from MS patients concurrent with MRI examination of the brain, and expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3 and CXCR4 by CD4 T cells and monocytes, proportions of Tr cells, as well as expression of CD45RO, CD95, CTLA-4, HLA-DR and interleukin (IL)-10 by Tr cells and non-Tr (CD25-) CD4 T cells was analyzed by flow cytometry. Surface expression of CXCR3 by CD4 T cells was downregulated in the group of patients with high lesion load (LL) on T2-weighted images and gadolinium (Gd)-enhancing lesions on T1-weighted images, compared to the group with high LL and no Gd-enhancing lesions, and to the group with low LL, suggesting internalization of CXCR3 due to the release of its chemokine ligand (IP-10/CXCL10) from active MS lesions. Proportions of Tr cells amongst all CD4 T cells, and expression of IL-10 by Tr cells were increased in the patients with high LL and Gd-enhancing lesions. These results suggest that there is correlation between MRI parameters, chemokine receptor expression and the status of circulating Tr cells in MS, but further studies need to discriminate between pathogenetically relevant and bystander phenomena.

Adult↗
PubMed2003

Predicting multiple sclerosis at optic neuritis onset.

Using multivariate analyses, individual risk of clinically definite multiple sclerosis (CDMS) after monosymptomatic optic neuritis (MON) was quantified in a prospective study with clinical MON onset during 1990-95 in Stockholm, Sweden. During a mean follow-up time of 3.8 years, the presence of MS-like brain magnetic resonance imaging (MRI) lesions and oligoclonal immunoglobulin (Ig) G bands in cerebrospinal fluid (CSF) were strong prognostic markers of CDMS, with relative hazard ratios of 4.68 [95% confidence interval (CI) 2.21-9.91] and 5.39 (95% CI 1.56-18.61), respectively. Age and season of clinical onset were also significant predictors, with relative hazard ratios of 1.76 (95% CI 1.02-3.04) and 2.21 (95% CI 1.13-3.98), respectively. Based on the above two strong predictors, individual probability of CDMS development after MON was calculated in a three-quarter sample drawn from a cohort, with completion of follow-up at three years. The highest probability, 0.66 (95% CI 0.48-0.80), was obtained for individuals presenting with three or more brain MRI lesions and oligoclonal bands in the CSF, and the lowest, 0.09 (95% CI 0.02-0.32), for those not presenting with these traits. Medium values, 0.29 (95% CI 0.13-0.53) and 0.32 (95% CI 0.07-0.73), were obtained for individuals discordant for the presence of brain MRI lesions and oligoclonal bands in the CSF. These predictions were validated in an external one-quarter sample.

Adult↗
PubMed2003

Differential recruitment of the coactivator proteins CREB-binding protein and steroid receptor coactivator-1 to peroxisome proliferator-activated receptor gamma/9-cis-retinoic acid receptor heterodimers by ligands present in oxidized low-density lipoprotein.

Peroxisome proliferator-activated receptor gamma (PPARgamma) colocalizes with oxidized low-density lipoprotein (LDL) in foam cells in atherosclerotic lesions. We have explored a potential role of oxidized fatty acids in LDL as PPARgamma activators. LDL from patients suffering from intermittent claudication due to atherosclerosis was analyzed using HPLC and gas chromatography/mass spectrophotometry and found to contain 9-hydroxy and 13-hydroxyoctadecadienoic acid (9- and 13-HODE), as well as 5-hydroxy-, 12-hydroxy- and 15-hydroxyeicosatetraenoic acid (5-, 12- and 15-HETE respectively). PPARgamma was potently activated by 13(S)-HODE and 15(S)-HETE, as judged by transient transfection assays in macrophages or CV-1 cells. 5(S)- and 12(S)-HETE as well as 15-deoxy-Delta(12,14)-prostaglandin J(2) also activated PPARgamma but were less potent. Interestingly, the effect of the lipoxygenase products 13(S)-HODE and 15(S)-HETE as well as of the drug rosiglitazone were preferentially enhanced by the coactivator CREB-binding protein, whereas the effect of the cyclooxygenase product 15-deoxy-Delta(12,14)-prostaglandin J(2) was preferentially enhanced by steroid receptor coactivator-1. We interpret these results, which may have relevance to the pathogenesis of atherosclerosis, to indicate that the lipoxygenase products on the one hand and the cyclooxygenase product on the other exert specific effects on the transcription of target genes through differential coactivator recruitment by PPARgamma/9-cis retinoic acid receptor heterodimer complexes.

Aged↗
PubMed2002

Cerebrospinal fluid affects phenotype and functions of myeloid dendritic cells.

Myeloid (CD11c+) dendritic cells (DC) are present in cerebrospinal fluid (CSF), as well as in the meninges and choroid plexus. Functional studies of these DC are hindered or impossible. To obviate this problem, we investigated the effects of CSF supernatants from patients with non-inflammatory neurological diseases (NIND), multiple sclerosis (MS), bacterial meningitis (BM) and Lyme meningoencephalitis (LM) on immature monocyte-derived DC (moDC) from healthy donors. CSF supernatants caused maturation of moDC (MS > LM > NIND > BM), as reflected by a decrease in CD1a, and an increase in HLA-DR, CD80 and CD86 expression. The maturation effect of MS CSF and LM CSF could be blocked by anti-TNF-alpha MoAb or recombinant human IL-10. moDC cultured with BM CSF either remained immature or turned into CD14+ macrophage-like cells and were relatively inefficient at inducing T cell responses in vitro. In contrast, moDC cultured with LM CSF induced strong Th1 responses. Both BM CSF and LM CSF contained IFN-gamma, a cytokine that augments IL-12 production by moDC and hence should confer an ability to induce a Th1 response. However, BM CSF also contained high levels of IL-10, which could antagonize the effects of IFN-gamma on moDC. moDC cultured with MS CSF induced a higher production of IFN-gamma from T cells compared to moDC cultured with NIND CSF or BM CSF. In summary, soluble factors present in the CSF may influence the phenotype and functions of meningeal, choroid plexus and CSF DC which, in turn, may have an impact on the character of intrathecal T cell responses.

Cell Differentiation↗
PubMed2002

Multiple MAG peptides are recognized by circulating T and B lymphocytes in polyneuropathy and multiple sclerosis.

Abnormal immune responses to myelin associated glycoprotein (MAG), a component of myelin of the central and peripheral nervous system, have been suggested to play a role in the pathogenesis of multiple sclerosis (MS) and certain types of inflammatory polyneuropathy. To identify possible immunodominant MAG peptides in neuroinflammation, we examined T and B cell responses to five selected synthetic MAG peptides and myelin proteins in 21 patients with non-inflammatory polyneuropathy, 26 patients with MS, 10 optic neuritis patients and 17 healthy subjects. Enzyme-linked immunosorbent spot-forming cell assays were adopted, allowing the detection and enumeration of individual antigen responsive T and B cells in body fluids. Patients with polyneuropathy as well as those with MS had elevated levels of T and B cells recognizing MAG and its peptides. Any of the five MAG peptides under study functioned as immunodominant T and/or B cell epitope in individual subjects. None of the MAG peptides elicited a specific disease-associated T or B cell response. The enhanced T and B cell response to myelin components like MAG may play some role in initiation and/or progression of these diseases, but they could also represent secondary responses associated with myelin damage and indicate tolerization rather than autoaggressive immunity.

Adult↗
PubMed2001

Glatiramer acetate and IFN-beta act on dendritic cells in multiple sclerosis.

Glatiramer acetate (GA; Copolymer 1; Copaxone) and interferon-beta (IFN-beta) modulate the course of multiple sclerosis (MS), but probably by different mechanisms. GA, a mixture of synthetic peptides, is believed to act as an altered peptide ligand with inhibitory effects on autoreactive T cells and promoting Th2 cells. It is unknown whether GA affects dendritic cells (DCs), which, besides strong antigen presenting capacity, orchestrate Th1 and Th2 responses. IFN-beta inhibits IL-12 production by DCs over unknown mechanisms. This study was designed to investigate in vitro effects of GA and IFN-beta on the development and function of DCs from MS patients and healthy controls, and to explore their possible synergistic effects on DCs. DCs were generated from adherent blood mononuclear cells (MNCs). GA or IFN-beta or both, when added at initiation of DC cultures, rapidly promoted the development of adherent MNCs into floating, activated DCs as reflected by up-regulation of HLA-DR and CD86 expression. IFN-beta, but not GA, induced IL-3R expression on DCs. Compared to DCs from healthy controls, MS patients' DCs expressed higher levels of the myeloid DC marker CD1a and produced lower amounts of IL-10. GA reduced IL-12 production by DCs. IFN-beta also reduced IL-12, but increased IL-10 production by DCs from both MS patients and healthy controls. GA and IFN-beta synergistically suppressed CD1a and enhanced CD86 expression on MS DCs. These findings document novel mechanisms of action of GA and IFN-beta at the DC level in MS.

Adjuvants, Immunologic↗
PubMed2001

[Why researchers excluded women from their trial populations].

Women are still, but to a lesser extent than twenty years ago, excluded as subjects of medical research on diseases that are prevalent among both men and women. To discover the basis on which women were excluded, the research ethics committee requested a written explanation. In all, 26 such project applications were identified during 1997-1999 (2% of the total number of applications during the period). Most researchers had more than one reason for exclusion. Qualitative analysis revealed that these explanations could be grouped into three categories, depending on whether women were excluded for scientific, historical or economic reasons. The scientific reasons correspond mainly to a lack of pertinent knowledge of the physiology and metabolism of women of childbearing age. Consequently, results lacked external validity. Perhaps the lack of knowledge of women's physiology and metabolism could be explained by a lack of female experimental animals in pre-clinical studies. One notes however a general concern not to harm women of childbearing age. The historical reasons underlie the tendency to repeat studies on former study populations that happened to be composed of men. Finally, tight research budgets restricted the participation of women but not of men. The Swedish Medical Research Council issued a policy document in 1998 to the effect that research ethics committees could require additional information concerning choice of study population. This study demonstrates an avoidable occurrence of gender bias in medical research.

Clinical Trials as Topic↗
PubMed2001

IL-12/IL-12R system in multiple sclerosis.

IL-12/IL-12 receptor (IL-12R) system orchestrates the Th1 pathway of the immune system by maintaining one of the major bridges between innate and adaptive immune responses. Here, we studied both sides of this system in patients with multiple sclerosis (MS) and in controls. MS patients displayed elevated IL-12Rbeta1 and IL-12Rbeta2 expression on PHA-activated T cells compared to healthy subjects. Higher percentages of IL-12Rbeta1 and IL-12Rbeta2 positive T cells in cerebrospinal fluid (CSF) compared to blood were observed both in MS and other neurological diseases (OND). In contrast, numbers of IL-12 secreting blood mononuclear cells (MNC) were similar in MS and controls. The functional importance of high IL-12Rbeta2 in MS was underlined by the finding that IL-12 stimulated IFN-gamma production and proliferation of PHA-activated T cells correlated with levels of IL-12Rbeta2 expression. Our data indicates a dysregulation of the IL-12/IL-12R system in MS. It is suggested that even in the absence of increased IL-12 levels, the net effect of IL-12 might be augmented in MS by elevated expression of its receptor.

Adult↗
PubMed2001

Clues to the immunopathogenesis of multiple sclerosis by investigating untreated patients during the very early stage of disease.

Plethora of abnormalities of the immune system has been described in multiple sclerosis (MS). They include a number of myelin antigens (e.g. MBP, MOG, PLP, MAG), the presence of reactive T cells in blood and, further enriched, in the cerebrospinal fluid (CSF), large numbers of B cells in the CSF secreting antibodies of multiple but unknown specificities, an increase of mononuclear cells (MNC) expressing and secreting both pro- and anti-inflammatory cytokines, including Th1 cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-6, the Th2 related IL-4 and IL-10, and the Th3-driven TGF-beta, elevated numbers of MNC in both blood and CSF expressing a spectrum of metalloproteinases and their inhibitors, as well as many other aberrations. However, no consistent patterns have emerged that relate any, of these findings to clinical variables such as exacerbations, duration of disease, disability, or lesions in the central nervous system (CNS) detected at magnetic resonance imaging. In order to elucidate the relevance of these immunological abnormalities in the pathogenesis of MS, my colleagues and I studied patients with acute monosymptomatic optic neuritis (ON) and compared them with patients with clinically definite MS (CDMS). The patients have not been treated and have not received corticosteroids or interferon-beta. When comparing these two groups, we were unable to identify any differences in any of the variables mentioned. Thus, very early MS, as represented by ON, shows the same full-blown pattern of immunological abnormalities seen in CDMS. Furthermore, a complete epitope spread affecting MBP, MOG, PLP, MAG and other myelin components is already present in ON. Whether any of these alterations play a pathogenetic role is still unsettled.

Brain↗
PubMed2001

Cysteine proteinases in chondrosarcomas.

The aim of the present study was to define the role of cathepsins B, H, K, L and S in the pathogenesis of human chondrosarcomas. For this purpose 40 tumour samples obtained from 12 patients with the diagnosis of conventional chondrosarcoma were systematically investigated for the expression of cathepsin mRNAs by Northern hybridisation, and for immunohistochemical localisation of the proteins. Northern analysis demonstrated the highest levels of cathepsins B and L in a recurring grade 1 chondrosarcoma, and in a grade 3 chondrosarcoma and in fibrous histiocytomas. Increased expression of cathepsin K mRNA was seen in seven chondrosarcomas, as well as in control tumours; fibrous histiocytomas, osteosarcomas, enchondromas and a giant cell tumour of bone. Cathepsin L was immunolocalised within the large chondrocytes, while cathepsin K was predominantly localised in large multinucleated osteoclastic cells and in some hypertrophic chondrocytes. These results suggest that chondrosarcoma can be included in the growing list of tumours, where cathepsins may well be involved in tumour progression. The simultaneous upregulation of cathepsins B and L, together with matrix metalloproteinase-13, and the association of cathepsin K with negative prognostic parameters suggests that an aggressive biological behaviour of chondrosarcoma may be related to the synthesis of cysteine proteinases and activation of other proteolytic enzymes. If this turns out to be the case, cathepsin inhibitors could provide the much needed adjuvant therapy for chondrosarcomas.

Adult↗
PubMed2001

Optic neuritis and multiple sclerosis.

PURPOSE: Review of the association between optic neuritis (ON) and multiple sclerosis (MS). RESULTS: MS often presents as acute unilateral ON. While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. With more and more well-informed patients and the emerging pharmacotheraphy for MS, the distinction between those patients with ON who have MS and those who do not, has become more important than ever before. Recently, a large randomized clinical trial on patients with ON or other clinically isolated syndromes suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain, found that treatment with recombinant interferon-beta-1a is beneficial by reducing the development of CDMS. CONCLUSION: Ophthalmologists should refer their patients with acute ON to a neurologist for MS-directed investigations and decisions regarding early institution of disease modifying therapy.

Acute Disease↗
PubMed2001

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human chondrosarcomas.

The aim of the present study was to characterise the ability of malignant chondrosarcomas to invade normal bone by analysing their production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). For this purpose 12 chondrosarcomas were investigated for the expression of mRNAs for several MMPs and all 4 TIMPs by Northern hybridisation, and for immunohistochemical localisation of the proteins. A characteristic finding of these analyses was increased expression of MMP-13, MMP-14 and TIMP-2 mRNAs in chondrosarcomas when compared with nonmalignant control samples. Individual chondrosarcomas also exhibited elevated levels of MMP-1, MMP-7 and MMP-9 mRNAs. The results of Northern hybridisations were supported by immunohistochemical stainings of the corresponding tumour areas for MMP-2, MMP-14 and TIMP-2, further suggesting that these may have prognostic value for determining whether individual chondrosarcomas are locally aggressive or have a probability of recurrence. Another finding of the present study was a marked heterogeneity in histologic appearance and gene expression of the chondrosarcomas, emphasising the importance of analysing several areas of these tumours to get representative results. These findings suggest that analysis of MMPs could be a useful diagnostic indicator in patients with cartilaginous tumours and could help in differentiating between a low-grade malignant chondrosarcoma and a benign growing enchondroma.

Adolescent↗
PubMed2001

Dynamic sonography with provocation of pain for diagnosis of symptomatic mobile kidneys.

OBJECTIVE: To evaluate the results of nephropexy in patients with a diagnosis of symptomatic mobile kidney that had been established by dynamic sonography with provocation of pain. DESIGN: Prospective study. SETTING: University hospital, Sweden. SUBJECTS: 19 consecutive patients with symptomatic right-sided mobile kidney and 6 controls who had urographically mobile kidneys but no pain. INTERVENTIONS: Dynamic sonography and dislocation of the kidney by manipulation. All 19 patients experienced pain on manipulation and the 6 controls did not. The 19 patients were treated by nephropexy and followed for at least four years postoperatively. MAIN OUTCOME MEASURE: Relief of pain after nephropexy. RESULTS: In 16/19 patients the pain was relieved by nephropexy. CONCLUSION: Dynamic ultrasound is useful in correlating the abnormal position of the kidney with pain, and successfully indicates those patients whose symptoms will be relieved by nephropexy.

Adult↗