PubMed Health⌕ Search

Biomedical subjects

P Fredman

Publications and source records attributed to P Fredman.

At least 19 recordsLinked to original sources
PubMed2002

White matter changes in normal pressure hydrocephalus and Binswanger disease: specificity, predictive value and correlations to axonal degeneration and demyelination.

OBJECTIVES: To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD). MATERIALS AND METHODS: PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients. RESULTS: No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P < 0.05). CSF sulphatide correlated positively with the amount of DWMH (P < 0.05) while NFL was correlated to both PVH and DWMH (P < 0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P < 0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance. CONCLUSION: In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.

Aged↗
PubMed2002

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations.

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect.

Animals↗
PubMed2001

Haptoglobins as markers of blood-CSF barrier dysfunction: the findings in normal CSF.

Cerebrospinal fluid from 39 healthy individuals showed evidence for increasing blood-CSF barrier permeability with age, and confirmed that haptoglobins are more sensitive but less predictive markers of barrier permeability than total protein. Haptoglobin (Hp) species were identified by polyacrylamide gel electrophoresis followed by immunoblotting. Hp 1-1 (35 A, 85 kDa) was detected in all (9/9) subjects who exhibited this phenotype. Hp 2-1 (42 A, 120 kDa) was detected in 53% (8/15) of subjects in whom Hp 2-1 was the phenotype. Hp 2-2 (54 A, 160 kDa) was detected in only 20% (3/15) of subjects who exhibited this phenotype. The likelihood of detecting any haptoglobin species corresponded to the molecular size and the consequent resistance offered by the barrier. Among younger subjects aged < or =45 years, a significant difference in incidence occurred between the two smaller species Hp 1-1 and Hp 2-1. However, among those aged >45, the significant difference in incidence was between the two larger species Hp 2-1 and Hp 2-2. The incidence of detection among those with Hp 2-1 phenotypes was higher in the older age group. The increased likelihood of detecting haptoglobins with age is in keeping with the notion that barrier function is compromised by age, and also indicates that Hp 2-1 and Hp 2-2 are sensitive markers of barrier function. The appreciable incidence of haptoglobins in normal CSF, even of the larger species, suggests reservation in assuming that their presence signifies barrier damage.

Adolescent↗
PubMed2001

IL-10 and IFN-gamma in Guillain-Barré syndrome. Network Members of the Swedish Epidemiological Study Group.

Guillain-Barré syndrome (GBS) is an acute inflammatory disease affecting myelin and axons of the peripheral nervous system (PNS). GBS is considered to be caused by breakdown of tolerance to autoantigens of the PNS. The involvement of cytokines in GBS and in relation to treatment with high dose intravenous immunoglobulin (IvIg) is incompletely known. We studied the temporal profiles of IL-10 and IFN-gamma-secreting blood mononuclear cells (MNC) over the course of GBS, using enzyme-linked immunospot (ELISPOT) assays. Pretreatment levels of blood MNC spontaneously secreting IL-10 were higher in the acute phase of GBS than in control patients with aseptic meningitis, other neurological diseases, diabetic neuropathy and healthy subjects. Levels of IFN-gamma-secreting blood MNC were not increased over the course of GBS. Patients treated with IvIg had lower numbers of IL-10-secreting MNC compared to untreated patients. High levels of IL-10-secreting MNC correlated with serum anti-ganglioside IgM antibody levels, and with neurophysiological signs of axonal damage. The present data suggests that IFN-gamma is not involved in GBS pathogenesis, and IL-10 being up-regulated in the early phase of GBS and associated with axonal damage, may have a pathogenetic role in GBS.

Adult↗
PubMed2001

The glioma-associated gangliosides 3'-isoLM1, GD3 and GM2 show selective area expression in human glioblastoma xenografts in nude rat brains.

This work describes the in vivo expression and distribution of glioma-associated gangliosides (GD3, GM2, 3'-isoLM1) in a novel human brain tumour nude rat xenograft model. In this model, the tumours, which are established directly from human glioblastoma biopsies, show extensive infiltrative growth within the rat brain. This model therefore provides an opportunity to study ganglioside expression not only within the macroscopic tumour, but also in brain areas with tumour cell infiltration. The ganglioside expression was studied by confocal microscopy of immunostained brain sections using antiganglioside monoclonal antibodies. Xenografts from four human glioblastoma multiformes were established in rats and the brains removed after 3-4 months. Ganglioside GD3 was expressed in the tumour parenchyma while ganglioside 3'-isoLM1 was more abundantly expressed in the periphery of the tumour associated with areas of tumour cell invasion. GM2 expression was only seen in one tumour, where it was located within the main tumour mass. Double staining with a pan antihuman monoclonal antibody (3B4) and the antiganglioside monoclonal antibodies confirmed that the ganglioside expression was associated with tumour cells. This work supports the concept of different biological roles for individual gangliosides and indicates that antibodies or ligands directed against GD3 and 3'-isoLM1 might be complementary when applied in the treatment of human glioblastomas.

Animals↗
PubMed2001

Sulfatide promotes the folding of proinsulin, preserves insulin crystals, and mediates its monomerization.

Sulfatide is a glycolipid that has been associated with insulin-dependent diabetes mellitus. It is present in the islets of Langerhans and follows the same intracellular route as insulin. However, the role of sulfatide in the beta cell has been unclear. Here we present evidence suggesting that sulfatide promotes the folding of reduced proinsulin, indicating that sulfatide possesses molecular chaperone activity. Sulfatide associates with insulin by binding to the insulin domain A8--A10 and most likely by interacting with the hydrophobic side chains of the dimer-forming part of the insulin B-chain. Sulfatide has a dual effect on insulin. It substantially reduces deterioration of insulin hexamer crystals at pH 5.5, conferring stability comparable to those in beta cell granules. Sulfatide also mediates the conversion of insulin hexamers to the biological active monomers at neutral pH, the pH at the beta-cell surface. Finally, we report that inhibition of sulfatide synthesis with chloroquine and fumonisine B1 leads to inhibition of insulin granule formation in vivo. Our observations suggest that sulfatide plays a key role in the folding of proinsulin, in the maintenance of insulin structure, and in the monomerization process.

Animals↗
PubMed2001

Patients with Primary brain tumours have elevated serum titres of antibodies to the myelin glycolipid sulphatide.

Primary and metastatic brain tumours may result in an altered exposure of normal cellular components to the immune system inducing an immune response measurable in autoantibodies. One potential immunogenic molecule is sulphatide, the major acidic glycolipid in myelin. Thirty-eight sera from 31 patients with primary and metastatic brain tumours have, therefore, been analyzed for the presence of antisulphatide antibodies by an ELISA performed on thin layer chromatography plates. Twenty-eight of the thirty-eight sera (74%) showed a positive antibody titre to sulphatide. The antibody titres were significantly higher (p < 0.01) in sera from patients with primary brain tumours than in sera from those with metastases. The study lends support to the possibility that antisulphatide antibodies could contribute to tissue damage and this might facilitate the invasive growth in primary brain tumours by demyelination. However, the pathogenic significance of these autoantibodies remains to be further elucidated.

Adolescent↗
PubMed2001

Treatment with sulfatide or its precursor, galactosylceramide, prevents diabetes in NOD mice.

Sulfatide (3'sulfogalactosylceramide) is a glycosphingolipid present within the nervous system and in the islets of Langerhans. Anti-sulfatide antibodies have been observed in both pre-diabetic and newly diagnosed type 1 diabetic patients. The aim of this study was to test in vivo, the therapeutic effect of sulfatide on the development of diabetes in the NOD mouse. In four separate experiments diabetogenic splenocytes from newly diabetic NOD mice were injected iv into 7-8 week old irradiated (700R) female NOD mice (4-10 million cells/mouse). Each experiment consisted of four treatment groups to which the mice were randomly divided: 1) sulfatide; 2) galactosylceramide (the precursor to sulfatide without sulfate); 3) GM1, a glycosphingolipid negatively charged as sulfatide but with a different sugar composition; and 4) phosphate buffered saline (PBS). The mice received 100 microg glycosphingolipid iv on the day of cell transfer and 1-3 times thereafter at four day intervals, and were screened for diabetes three times a week the next 52 days. Among all the 35 sulfatide-treated mice 54% became diabetic compared to 93 % of 43 PBS-treated animals (p < 0.00001). Correspondingly, galactosylceramide reduced diabetes incidence to 52% (25 mice, p < 0.00001). On the other hand, 86% of GM1-treated mice (n=28) became diabetic indicating that no effect was obtained by this glycosphingolipid. In two experiments in which less spleen cells were transferred (4-5 mill.) and glycosphingolipids were given 4 times, 35% of the sulfatide-treated animals (n = 17) developed diabetes compared to 85% of PBS-treated mice (n = 20, p < 0.001). A robust proliferative response to sulfatide, but none to GM1, was observed when spleen cells were rechallenged with glycosphingolipid in vitro. Thus, like insulin and GAD, sulfatide is able to prevent diabetes in NOD mice.

Adoptive Transfer↗
PubMed2000

Immunostaining of ganglioside GD1b, GD3 and GM1 in rat cerebellum: cellular layer and cell type specific associations.

We have studied the cellular distribution of gangliosides GD1b, GD3 and GM1 in rat cerebellum by immunostaining, using monoclonal antibodies and confocal microscopy. Antibodies against astroglial, neuronal and synaptic vesicle associated molecules were used for colocalization analyses. In the gray matter, the anti-GD1b antibody stained thin strands in the molecular layer (ML), interpreted as Bergman glia fibers based on colocalized staining with anti-glial fibrillary acidic protein (GFAP). The neuropil in the granule (GL) and Purkinje (PL) cell layers was also anti-GD1b positive. The anti-GD3 antibody stained the ML, the neuropil in the GL and PL and also the granule and Purkinje cell bodies, appearing intracytoplasmically and vesicle associated. Anti-GD1b and anti-GD3 staining in the GL glomeruli were colocalized with anti-synaptophysin staining. The anti-GM1 antibody stained cell bodies in the ML but they could not be characterized in colocalization experiments. The GL and PL were not stained with the anti-GM1 antibody. In the white matter, different staining patterns were seen for the gangliosides, the anti-GM1 staining being the most intense. This study shows cellular layer and cell type specific associations of the investigated gangliosides and localization of GD1b and GD3 at synaptic sites, warranting further studies on their role in synaptic mechanisms.

Animals↗
PubMed2000

Reactivity of monoclonal antibodies with ganglioside antigens in human small cell lung cancer tissues.

Gangliosides on tumor cells have been suggested as potential target antigens for specific immunotherapy in various types of cancer including small cell lung cancer (SCLC). In this study we have compared the expression of three gangliosides that have been described as tumor-associated antigens, FucGM1, GM2 and GD3 in SCLC tissue specimens collected at autopsy, using a double-layer immunofluorescence staining method and specific monoclonal antibodies (Mabs) directed against these ganliosides. We found expression of FucGM1, GD3 and GM2 in (70% (n=20), 60% (n=15) and 40% (n75% of the tumor cells in all lesions from the same patient (five of eight cases). Our results indicate that FucGM1 is a relevant ganglioside antigen in SCLC, and suggest that specific immunotherapy involving more than one ganglioside antigen in SCLC should at least include FucGM1 and GD3.

Antibodies, Monoclonal↗
PubMed2000

Measurement of apolipoprotein E (apoE) in cerebrospinal fluid.

Apolipoprotein E (apoE) is a protein involved in transport of lipids and has been implicated to play an important role in regeneration after nerve injury. Determination of apoE in cerebrospinal fluid (CSF) thus have a potential interest when studying different forms of brain damage and as a marker of ongoing regenerative processes in the brain. However, previous studies on CSF-ApoE in Alzheimer's disease (AD) have given inconclusive results. Such inconsistent results might be related to confounding factors interfering with sample handling and/or analyses, which have not been fully elucidated. We therefore examined different potential confounding factors for analyses of apoE in CSF and also developed a new enzyme linked immunosorbent assay (ELISA). The hydrophobic character of ApoE resulted in adsorption to different types of test tubes commonly used for collection of CSF at lumbar puncture, resulting in falsely low levels. This makes CSF handling critical, especially if samples are taken in different types of tubes, or is transferred to new tubes. Taking this confounding factors in consideration and analysing patient and control CSF handled in the same way and using the new ELISA, we could confirm our previous finding of reduced levels of ApoE in AD, (3.4 +/- 1.3 mg/l) compared with controls (4.5 +/- 2.7 mg/l) (p = 0.045). Both in the AD and in the control group, higher levels of CSF-ApoE was found in individuals possessing the ApoE4 alleles. Our results support that CSF-ApoE is reduced in AD, and that handling of CSF is a critical factor, which may explain the discrepant results from previous studies. Differences in the amount of patients and controls possessing the ApoE4 allele included might also increase the variance between different studies.

Aged↗
PubMed2000

Monoclonal anti-GD3 antibodies selectively inhibit the proliferation of human malignant glioma cells in vitro.

The frequently occurring alteration of ganglioside expression in tumor cells has been implicated to play a role in the uncontrolled growth of these cells; antibodies to such gangliosides might affect tumor cell growth. We have studied the effect of IgM monoclonal antibodies to two glioma-associated gangliosides, GD3 and GM2, on cell proliferation of four human glioma cell lines and one renal tumor cell line. Of the two anti-ganglioside antibodies tested, only the anti-GD3 antibody resulted in a significant (p<0.005) inhibition of cell proliferation as measured by thymidine incorporation and Brd-U labeling, after 24h incubation. The effect was not dependent on any serum factor and no increased cell death was observed. All cell lines contained higher or similar amounts of GM2 than GD3, and both antigens were shown to be expressed on the cell surface and accessible to antibodies. The selective effect of anti-GD3 antibodies as contrasted to the inactivity of anti-GM2 antibodies suggests a possible role for ganglioside GD3 in tumor cell proliferation.

Antibodies, Monoclonal↗
PubMed2000

The glycosphingolipid sulfatide in the islets of Langerhans in rat pancreas is processed through recycling: possible involvement in insulin trafficking.

In previous studies we have shown that sulfatide (galactosylceramide-3-O-sulfate), in various species, is present in the insulin-producing cells in pancreatic islets of Langerhans. In this study the synthesis of sulfatide in the islets has been investigated by pulse chase labeling at varying glucose levels and in the presence or absence of the glycosphingolipid synthesis inhibitory agents, Brefeldin A, fumonisin B1 and chloroquine and the distribution of sulfatide by immune-electronmicroscopy. The data showed that (1) sulfatide was produced in islets of Langerhans, (2) the main pathway for synthesis was through recycling involving partial degradation in the lysosome, and that (3) high glucose levels, although not primarily reflected in an increased synthesis of sulfatide, lead to an increased expression of mRNA for the UDP-galactose:ceramide galactosyltransferase, producing the immediate precursor of sulfatide. Furthermore, mass spectrometry analyses revealed a high proportion of short chain fatty acids, C16:0 (50%) and no hydroxylated forms and thus special physicochemical properties, indicating important differences between pancreatic and brain/neural sulfatide. Immune electron microscopy revealed an intracellular expression of sulfatide in the secretory granules, the Golgi network and the lysosomes of the islets. These results indicate that sulfatide follows the same intracellular route as insulin and suggest a functional association between these molecules. We have raised the hypothesis that sulfatide possibly plays a role in the trafficking of insulin in the islets of Langerhans in rat pancreas.

Animals↗
PubMed2000

CSF sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy.

OBJECTIVES: To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features. METHODS: CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH. RESULTS: The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p<0.001). 5-HIAA, GABA, and VIP in CSF were higher in patients with SAE than in patients with NPH. The patients with NPH with cerebrovascular aetiology had higher sulfatide concentrations and a poorer outcome after shunt surgery than patients with NPH with other aetiologies. CONCLUSIONS: The pathogenesis of the white matter changes in NPH and SAE is different and ischaemic white matter changes can be a part of the NPH state. The markedly increased CSF sulfatide concentrations in patients with SAE indicate ongoing demyelination as an important pathophysiological feature of SAE. The CSF sulfatide concentration distinguished between patients with SAE and those with NPH with a sensitivity of 74% and a specificity of 94%, making it an important diagnostic marker.

Adult↗
PubMed1999

Recovery of severe sciatica.

STUDY DESIGN: A prospective study of patients with acute severe sciatica. OBJECTIVES: To 1) describe the characteristics of patients with acute severe sciatica and the agreement among different diagnostic tests, 2) describe overall recovery during 1 year in terms of perceived disability, and pain, and 3) explore acute-phase predictors of failure to recover at 1 year. SUMMARY OF BACKGROUND DATA: The development of imaging techniques has been very impressive during recent decades. However, different authors have highlighted the prevalence of abnormal images among asymptomatic subjects. These findings increase the difficulty of interpreting the results from the diagnostic techniques used with each individual patient. Furthermore, other clinical and biopsychosocial variables need to be explored for their associations with recovery or failure to recover. This study aimed to explore those associations. METHODS: Consecutive patients admitted to the hospital for conservative management of severe acute sciatica were eligible for inclusion in the study. Patients were evaluated at admission, discharge, and 3, 6, and 12 months. All the visits included a standardized clinical examination and the completion of questionnaires that included items on demographics, pain, perceived disability, and quality of life. Imaging and blood samples were collected at the first visit, and an electromyogram was taken for sciatica lasting at least 3 weeks. RESULTS: The study included 82 consecutive patients (66% men) with a mean age of 43 +/- 10.3 years. The mean intensity of pain, on a visual analog scale of 0 to 100 (VAS) at Visit 1, was 73. The straight leg raising test was positive in 78% of the patients, with a mean value of 59 degrees +/- 18 degrees. The contralateral straight leg raising test was positive in 20% of the patients. Imaging was positive for disc herniation in 74% and electromyogram was positive in 62% of cases. These two diagnostic tests showed a good to excellent total agreement (58-87%) with the straight leg raising tests and the presence of radiating pain below the knee. The recovery of clinical symptoms and signs was observed mainly within the first 3 months. However, clinical recovery and perceived recovery was not complete in most cases. CONCLUSIONS: In most cases, there was good to excellent agreement among the different diagnostic tests. None of the tests was predictive of recovery. The presence of blood antibodies against 3'LM1 (IgM + IgG) and GD1a (IgM) was significantly associated (P < 0.023) with neurologic symptoms and signs. However, the meaning of these antibodies remains unclear. Only a minority of the patients (29%) had fully recovered after 12 months. Within the 1-year follow-up, one third of the patients had surgery.

Adult↗
PubMed1999

In vitro production of cytokines is influenced by sulfatide and its precursor galactosylceramide.

Effects of sulfatide and its precursor galactosylceramide (gal-cer) on the kinetics of production of cytokines were studied. In human mononuclear leucocytes, gal-cer but not sulfatide induced significantly increased amounts of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF) mRNA. In phytohemagglutinin-stimulated cultures, gal-cer increased the levels of IL-1beta and IL-6 mRNA and secreted IL-1beta and IL-6, while sulfatide decreased the amounts of IL-6 mRNA and secreted IL-6. Gal-cer also increased TNF secretion. In lipopolysaccharide-stimulated cells, sulfatide but not gal-cer decreased the secretion of IL-1beta and IL-10, a potent suppressor of production of many cytokines. Thus, sulfatide and gal-cer affect cytokine production differently, most likely at the level of gene expression. This may have implications in diseases where inflammatory cytokines play a pathogenic role.

Adult↗
PubMed1999

High levels in serum, but no signs of intrathecal synthesis of anti-sulfatide antibodies in HIV-1 infected individuals with or without central nervous system complications.

Myelin degeneration is commonly found in the central nervous system (CNS) of individuals infected with human immunodeficiency virus type 1 (HIV-1), especially in patients with HIV-1-associated dementia. We analysed cerebrospinal fluid (CSF) and serum samples from 25 HIV-1 infected individuals for the presence of antibodies directed against sulfatide, the major acidic glycosphingolipid in myelin. Nine of the patients had CNS complications, including 3 with HIV-1-associated dementia, and 16 had no neurological symptoms. Elevated titres of anti-sulfatide antibodies were found in serum from 24/25 HIV-1-infected individuals but in none of them in the CSF. Although the vast majority of HIV-1-infected individuals harbour autoantibodies directed against sulfatide in serum, the lack of detectable intrathecal production indicates that anti-sulfatide antibodies are not a major component in the pathogenesis of CNS myelin damage in HIV-1 infection.

AIDS Dementia Complex↗