Biomedical subjects

P Fredman

Publications and source records attributed to P Fredman.

At least 55 records · Page 3Linked to original sources

PubMed1997

The presence of foetal ganglioside antigens 3'-isoLM1 and 3'6'-isoLD1 in both glioma tissue and surrounding areas from human brain.

Glioma-associated gangliosides, in particular the expression of foetal gangliosides 3'-isoLM1 and 3'6'-isoLD1, have been investigated in biopsies from 44 patients with astrocytoma grade II, anaplastic astrocytoma, anaplastic oligodendrogliomas, oligodendrogliomas, and glioblastoma multiforme. The total ganglioside content decreased in proportion to the estimated number of tumour cells present in the biopsy. Ganglioside GD3 was increased in 17 of the tumour tissues and in 6 of the surrounding area specimens. In agreement with our previous studies, tumour specimens contained the lactoseries ganglioside 3'-isoLM1 and, as demonstrated for the first time, the disialylated form of the ganglioside, 3'6'-isoLD1. These gangliosides are in normal brain tissue restricted to the developmental period. Most frequent was the expression of ganglioside 3'-isoLM1 which was detected in 92% of the tumour specimens in concentrations varying between just detectable amounts to 13 nmol/g wet weight. In the area surrounding the macroscopic tumour tissue 78% of the specimens expressed 3'-isoLM1 and the values varied between just detectable amounts to 24 nmol/g wet weight. Ganglioside 3'6'-isoLD1 was found in 47% of the tumour biopsies and in only 17% of the specimens taken outside macroscopic tumour tissue. The values varied between non-detectable amounts to 40 nmol/g wet weight of tissue. The expression of 3'-isoLM1 correlated significantly (p < 0.01) to malignancy grade. For 3'6'-isoLD1 a significant (p < 0.05) difference was found between tumour and surrounding tissue. Likewise, 3'6'-isoLD1 correlated significantly (p < 0.05) to malignancy grade. The correlation between 3'-isoLM1 and 3'6'-isoLD1 to malignancy grade and the frequent expression of these gangliosides both in the tumour itself and in its surrounding area should encourage additional studies concerning their biological role in tumour disease.

Adolescent↗

PubMed1997

Increased activity of lysosomal glycohydrolases in glioma tissue and surrounding areas from human brain.

Increased metabolic activity represented by an increase in both anabolism and catabolism in tumours, including gliomas, is a well known phenomenon and utilised in positron emission tomography imaging of tumours. In this study lysosomal enzyme activities of some glycohydrolases were investigated in glioma tissue from human brain. Tumour tissue (ten cases) and brain tissue surrounding the tumour tissue (seven cases) from patients with a histopathological diagnosis of glioblastoma multiforme or anaplastic astrocytoma were analysed for activity of the lysosomal enzymes galactosylceramidase, glucosylceramidase, beta-galactosidase, beta-N-acetyl-glucosaminidase, beta-glucuronidase and acid phosphatase. All of the investigated lysosomal enzymes except galactosylceramidase showed increased activity compared with that in normal brain tissue. Moreover, despite sparsity of tumour cells the specimens taken from surrounding areas showed elevated activities of the same enzymes. The findings indicate an upregulation of the activity not only in tumour but also in normal cells of the surrounding area.

Adolescent↗

PubMed1997

Monosialoganglioside (GM1) immunofluorescence in rat spinal roots studied with a monoclonal antibody.

Gangliosides are characteristic glycolipid components of plasma cell membranes, especially enriched in the CNS and PNS. In some diseases involving the PNS, in particular motor neuropathies associated with conduction block, IgM autoantibodies against ganglioside GM1 have been implicated as a pathogenic factor. In order to study the GM1 distribution in peripheral nerves we have investigated its in situ localization using a new anti-GM1 monoclonal antibody, GM1:1. Immunization and production of the monoclonal antibody was made by common protocols and binding specificity was investigated by using structurally related glycolipids and modified GM1-molecules. The result showed that an alpha 2-3 bound sialic acid together with a terminal galactose moiety were essential for GM1:1 binding. In situ localization of GM1 in rat dorsal and ventral spinal roots was investigated by conventional immunomicroscopy. GM1 immunoreactivity was the same in both roots and appeared like a finely granular, in places confluent, material confined to Schmidt-Lanterman's incisures, to myelin sheath paranodal end segments and to some extent to the abaxonal Schwann cell cytoplasm; all of these structures are likely to be the target for GM1 antibodies in peripheral neuropathies. Nodal gaps and fibre contours showed a weak non-specific fluorescence. The localization of GM1 to the incisures of Schmidt-Lanterman and the paranodal end segments of the myelin sheaths might indicate a role of gangliosides as adhesion molecules.

Animals↗

PubMed1997

Glycosphingolipids as potential diagnostic markers and/or antigens in neurological disorders.

Glycosphingolipids are most abundant in the nervous system within which are developmental, regional, structural and cellular differences regarding their composition. The are shedded to the cerebrospinal fluid and thus potential markers for pathogenic alterations in the brain, such as developmental abnormalities, demyelination, gliosis, neuronal cell destruction. The glycosphingolipids have also been found to be antigens in autoimmune processes involving the nervous system, in particular in peripheral neuropathies like Guillain Barré syndrome, multifocal motor neuropathy etc. The immune response might have been triggered by infectious agents with an antigen epitope which mimic the glycosphingolipid or by a primary nerve tissue damage leading to release of glycosphingolipids. There is a series of support for a clinical significance of cerebrospinal fluid glycosphingolipid determinations and the presence of anti-glycosphingolipid antibodies but this has to be further explored. This paper is a mini review of the state of the art and discuss methodological aspects and improvements that might help to explore the relevance of glycosphingolipids in neurological disorders.

Animals↗

PubMed1997

Increased levels of cholesterol esters in glioma tissue and surrounding areas of human brain.

The proliferation of glioma cells requires cholesterol, which could be provided by synthesis within the cells or by uptake of cholesterol esters in particles of Low Density Lipoprotein (LDL). Cholesterol esters and cholesterol were therefore analysed in human glioma tissue, its surrounding areas and serum from 40 patients. The analyses revealed an increased concentration of cholesterol esters up to 100 times (0.1-10 mumol/g) in both tumour-tissue and surrounding areas compared with control material (< 0.1 mumol/g). The analyses also demonstrated that cholesterol esters in tumour tissue eminated mainly from serum. The cholesterol concentrations were significantly lower in tumour tissue compared with surrounding areas as expected. These results indicate that tumour cell proliferation utilises serum derived cholesterol esters presumably carried by LDL particles.

Adolescent↗

PubMed1997

Increased cerebrospinal fluid ganglioside GM1 concentrations indicating neuronal involvement in all stages of HIV-1 infection.

UNLABELLED: Measurements of cerebrospinal fluid (CSF) concentrations of gangliosides can be used as markers of central nervous system (CNS) neuronal involvement. We have analysed the CSF concentrations of the four major brain gangliosides GM1, GD1a, GD1b, and GT1b at different stages of HIV-1 infection. CSF samples were collected from 44 HIV-1-infected patients and from 24 HIV-negative, healthy controls. A significantly higher mean CSF concentration of the ganglioside GM1 was found in HIV-1-infected patients than in HIV-negative controls (27 and 19 nmol/l, respectively, P<0.01). The HIV-infected patients also had a higher mean GM1 proportion of the total ganglioside concentration (11% compared with 8.5%, P < 0.01). Nine out of 27 patients with asymptomatic HIV-1 infection, three of ten with AIDS without neurological complications, and three of seven with AIDS dementia complex had CSF GM1 concentrations above the mean+2SD in the HIV-negative control group. CONCLUSION: Biochemical signs of ongoing neuronal involvement could be found in about one third of HIV-1-infected patients. The same frequency was found regardless of stage, although the highest levels of CSF gangliosides were found in patients with AIDS.

AIDS Dementia Complex↗

PubMed1996

Sulfatide is expressed in both erythrocytes and platelets of bovine origin.

A novel sulfated glycosphingolipid containing a sulfated galactosyl residue was isolated from bovine erythrocyte ghosts, and purified to homogeneity by column chromatography on DEAE-Sephadex and silica beads. Structural characterization included compositional analyses, permethylation studies, proton nuclear magnetic resonance (NMR) spectroscopy, negative secondary ion mass spectrometry (SIMS), solvolysis and immunostaining on thin-layer chromatogram. As a result, the structure of this glycolipid is proposed as HSO3-Gal beta 1-1 Cer. The ceramide portion contained d18:1, d18:0 and t18:0, and the predominant fatty acid consisted of palmitate and palmitate with a hydroxy group, as deduced by both compositional analysis and negative SIMS mass spectrometry. The component of this glycosphingolipid probably originates from erythrocytes and platelets as indicated by the results of flow cytometry analysis using Sulph I monoclonal antibody. The yield of galactosyl sulfatide was about 0.37 mg/kg wet bovine erythrocyte membranes, about three times that of human kidney. Our results strongly suggest that galactosylceramide sulfate on erythroid cells may play an important biological role in cell to cell interaction and recognition.

Animals↗

PubMed1996

Elevated cerebrospinal fluid sulfatide concentrations as a sign of increased metabolic turnover of myelin in HIV type I infection.

Cerebrospinal fluid (CSF) sulfatide concentrations were analyzed in 18 patients with asymptomatic HIV-1 infection, in 16 patients with AIDS who were free from opportunistic infections in the central nervous system (CNS), in 12 HIV-1-infected patients with opportunistic CNS infections or lymphoma, and in 19 HIV-negative controls, by thin-layer chromatography overlay technique using an antisulfatide antibody to estimate the metabolic turnover of myelin. The majority of asymptomatic HIV-1-infected patients had normal CSF sulfatide concentrations, but the mean CSF sulfatide concentration was still elevated compared to that in HIV-negative controls (152 compared to 99 nmol/liter, p < 0.05). The CSF sulfatide concentrations in the AIDS group (mean 395 nmol/liter) were significantly increased compared to those in asymptomatic HIV-1-infected patients (p < 0.01) and in HIV-negative controls (p < 0.001), but did not differ significantly between patients with and without dementia. Increased CSF sulfatide concentrations were also found in patients with opportunistic infection or lymphoma in the CNS. In the entire study population, the sulfatide levels were associated with blood-brain barrier function, but not with intrathecal immunoglobulin production or with positive HIV isolations from CSF. Thus, signs of white matter changes, measured as increased CSF sulfatide concentrations, could be found in some asymptomatic HIV-1-infected patients, but the highest levels were seen in patients with AIDS.

AIDS-Related Opportunistic Infections↗

PubMed1996

Presence of sulphatide (3'-sulphogalactosylceramide) in pericytes in the choroid layer of the eye: sharing of this glycolipid autoantigen with islets of Langerhans.

The aim of the study was to investigate the distribution in the eye of sulphatide, an acid glycolipid which has previously been demonstrated in islets of Langerhans, nervous tissue and in kidney glomeruli of diabetic patients, and against which antibodies have been found in patients with newly diagnosed insulin-dependent diabetes mellitus. A specific monoclonal antibody, Sulph I, was used for detection of sulphatide by thin-layer chromatography, and light and electron microscope immunohistochemistry. A distinct, patchy staining was found in the choroid layer and the ciliary processes. The antigen was confirmed to be sulphatide and its concentration in human eyes was 30 nmol sulphatide/g wet tissue. By electron microscopy, anti-sulphatide choroid labelling was demonstrated in pericytes and in smooth muscle cells surrounding vessels. No Sulph I-negative pericytes were seen. Double labelling with Sulph I and anti-smooth muscle actin revealed that only pericytes in the eye contained sulphatide and not those in heart, lung, liver, adrenal, spleen, lymph node, thymus, or pancreatic tissue. Thus, sharing of the autoantigen sulphatide has been demonstrated between islets of Langerhans and pericytes in the choroid layer of the eye.

Aged↗

PubMed1996

In vivo growth conditions suppress the expression of ganglioside GM2 and favour that of lacto series gangliosides in the human glioma D-54MG cell line.

The human glioma D-54MG cell line grown in vitro primarily expresses ganglio series gangliosides, particularly GM2. Subcutaneous injection of these cells into nude mice produced xenografts with an increased content of the human glioma-associated lacto series gangliosides, primarily 3'-isoLM1, an alteration that was dose dependent, with the highest dose (1 x 10(8)) resulting in a phenotype that was most like that of the inoculum. After one passage in vivo, the lacto series dominated and reached a proportional level that was kept throughout the 10 passages. The mRNA levels of the GM2-synthase clearly coincided with GM2 expression and was 20 times higher in cells grown in vitro than in those grown in vivo. These results support the view that ganglioside expression in human gliomas is strongly influenced by environmental factors.

Animals↗

PubMed1996

Sulphatide and its precursor galactosylceramide influence the production of cytokines in human mononuclear cells.

Sulphatide is expressed in the central and peripheral neural system, in islets of Langerhans, and in tissues affected by late diabetic complications. Autoantibodies to sulphatide are present in patients with insulin-dependent diabetes and the Guillain-Barré syndrome. Cytokines influence these disease processes, and we therefore studied whether sulphatide and its precursor galactosylceramide (gal-cer) influence the in vitro production of cytokines by blood mononuclear cells (MNC) originating from 15 healthy persons. Using lipopolysaccharide (LPS)-stimulated cells, sulphatide increased the IL-2 production (163 +/- 17% of controls without sulphatide, p = 0.02), and gal-cer increased the IL-1 alpha production (145 +/- 13%, p = 0.006), whereas neither gal-cer nor sulphatide had an effect on the production of IL-6, IL-10 or TNF alpha. When stimulating cells with phytohaemagglutinin (PHA), sulphatide decreased the production of IL-6 (88 +/- 5%, p = 0.009), IL-10 (66 +/- 3%, p = 0.000003), and TNF alpha (75 +/- 9% p = 0.02). Gal-cer, however, increased the production of IL-6 (188 +/- 13% p = 0.000006), and decreased the production of TNF beta (80 +/- 6%, p = 0.007). Neither gal-cer nor sulphatide had an effect on the production of IL-2 or IFN gamma from PHA-stimulated cells. Northern blot analysis using an IL-6 probe similarly showed an increased amount of IL-6 mRNA after gal-cer incubation (range 469%-150%, n = 3) of PHA-stimulated control. Thus, sulphatide and gal-cer influence the production of several cytokines thought to be involved in immunoinflammatory disease processes.

Cytokines↗

PubMed1996

Immunoglobulin M in cerebrospinal fluid: reference values derived from 111 healthy individuals 18-88 years of age.

The importance of immunoglobulin M (IgM) determination in cerebrospinal fluid (CSF) has increased parallel to the need for early diagnosis of infectious and inflammatory disorders of the central nervous system. Current reference values are based on analysis of CSF from 'reference groups' consisting of patients with psychiatric and/or neurological symptoms but without positive clinical findings. Therefore, accurate reference values for CSF IgM are of utmost importance. The present study presents reference values for IgM in CSF in a large sample (n = 111) of healthy individuals with an age span of 18-88 years. The upper reference limit, calculated as the 0.95 fractile, was 0.36 mg/l for CSF IgM, 0.40 for CSF/serum IgM ratio, and 0.045 for the IgM index. These parameters showed no significant difference between sexes nor any significant correlations with age. The correlations between CSF/serum albumin ratio and CSF/S IgM ratio were linear and statistically highly significant, suggesting that the IgM index values do not depend on the blood-CSF barrier function within the normal range of the CSF/serum albumin ratio.

Adolescent↗

PubMed1996

Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat.

The aim of the present study was to examine the glial cell response and the possible involvement of the complement cascade following a cerebral cortical contusion. The lesion was produced using a standardized weight-drop technique in adult rats. The blood-brain barrier was damaged, as demonstrated by a decrease of immunoreactivity for a tight junction protein normally expressed by endothelial cells of small vessels in the central nervous system. Increased immunoreactivity for microglial (OX42) and astroglial cells (glial fibrillary acidic protein), as well as macrophages expressing ED1-immunoreactivity (IR) were found in the vicinity of the lesion at all postoperative survival times (2-14 days). In the present study complement factor C3d- and C9-IR was found around the lesion, indicating that activation of the complement cascade had taken place. Furthermore, immunoreactivity for the putative complement inhibitor clusterin (sulfated glycoprotein-2) was found in some of the injured neurons. The contralateral hemisphere showed no evidence of the reaction found in the ipsilateral hemisphere. The balance between complement activation and complement inhibitors may have an impact on the degenerative components in the brain following traumatic injury and in particular on the events leading to nerve cell death.

Animals↗

PubMed1995

Detection of cerebrospinal fluid leakage by isoelectric focusing on polyacrylamide gels with silver staining using the PhastSystem.

Cerebrospinal fluid (CSF) leakage, which sometimes occurs after skull trauma, is a life-threatening condition. A prompt start with antibiotics and/or prompt surgical treatment of fistulas is essential to avoid severe complications. This requires a fast and reliable method for detecting CSF leakage. This paper describes a fast (< 2 h) method based on the identification of the tau protein (beta 2-transferrin) band(s). Tau protein is a brain-specific variant of transferrin that is characteristic of CSF. The method includes iso-electric focusing (IEF) on pre-cast polyacrylamide gels and silver staining using the PhastSystem, an automated instrument for electrophoresis and staining. In the present study, this technology was applied on 200 consecutive CSF samples, 32 of which were from healthy volunteers. Tau protein was detected in all CSF samples but 5 (2.5%), all of which were from patients with blood-brain barrier (BBB) damage. In these cases, the tau protein band was indistinct when direct silver staining was used. Therefore, immunofixation with an antitransferrin antibody was performed, and after that the tau protein band was easy to detect. The specificity of the method was high, since no brain-specific tau protein band was detected in serum, tears, saliva, or nasal secretion. As IEF of CSF using the PhastSystem is increasingly used as the routine method for detection of oligoclonal bands of IgG in neurological disorders, it could readily be used in the clinical (neuro) chemical laboratory also for the less frequent cases of suspected CSF leakage.

Adolescent↗

PubMed1995

Neonatal treatment of BB rats with sulphatide delays development of diabetes but does not change incidence.

Sulphatide is a newly described autoantigen in insulin-dependent diabetes mellitus; it is present in the islets of Langerhans, and anti-sulphatide antibodies are found in diabetic patients and in spontaneously diabetic BB rats. The aim of the study was to treat neonatal BB rats with sulphatide in order to induce tolerance and thereby possibly influence later diabetes development. One hundred and twelve newborn BB rats, divided into three groups, were treated once daily during the first 6 days of life with intrathymic injections of sulphatide, galactosyl-ceramide (which is similar to sulphatide but without sulphate) or phosphate buffer alone. Although the results showed no difference in diabetes incidence among the three groups, there was a delayed onset of diabetes in the sulphatide-treated group, which developed diabetes on average at 77 +/- 1 days of age, compared to 70 +/- 2 days (p < 0.02) for the galactosyl-ceramide-treated group and 70 +/- 1 days (p < 0.01) for the buffer-treated group. The degree of insulitis and the size of islets of Langerhans were studied histologically for the diabetic animals in all three groups; there were no significant differences although the sulphatide-treated group tended to have a more normal histology. The blood glucose levels for the diabetic BB rats were similar in all three groups. Thus, neonatal treatment with the diabetic autoantigen sulphatide at the chosen dosage does not influence the incidence of diabetes, but delays the onset of disease.

Animals↗

PubMed1994

Infection of vaginal and colonic epithelial cells by the human immunodeficiency virus type 1 is neutralized by antibodies raised against conserved epitopes in the envelope glycoprotein gp120.

The rectal and genital tract mucosae are considered to be major sites of entry for the human immunodeficiency virus (HIV) during sexual contact. We now demonstrate that vaginal epithelial cells can be infected by HIV type 1 (HIV-1) via a mechanism similar to that described for neuroglial cells and, more recently, for colorectal epithelial cells, involving initial interaction of the HIV-1 envelope glycoprotein gp120 with a cell-surface glycosphingolipid (sulfated lactosylceramide). A hyperimmune serum against gp120 was able to neutralize HIV-1 infection of vaginal epithelial cells. Site-directed immunization was employed to identify sites on gp120 recognized by antibodies neutralizing HIV-1 infection of vaginal and colonic epithelial cells. Hyperimmune sera were raised in monkeys against a series of 40 overlapping synthetic peptides covering the entire sequence of HIV-1 (HTLV-IIIB) gp120. Antisera raised against five synthetic peptides, corresponding to three relatively conserved regions and to the hypervariable region (V3 loop), efficiently neutralized HIV-1 infection of human vaginal epithelial cells in vitro. Similar results were obtained with the colonic cells. Hyperimmune sera to all five peptides have been shown earlier to neutralize HIV-1 infectivity in CD4+ T cells. These results have obvious implications for the design of mucosal subunit vaccines against sexually transmitted HIV-1 infections.

Base Sequence↗

PubMed1994

Cerebrospinal fluid apolipoprotein E is reduced in Alzheimer's disease.

Apolipoprotein E (ApoE) has been implicated in the pathogenesis of Alzheimer's disease (AD). ApoE is synthesized within the brain and has been suggested to be involved in the re-utilization of membrane lipids during neuronal repair and remyelination after injury. Spherical ApoE-containing lipoprotein particles are found in the cerebrospinal fluid (CSF). To study further the pathogenetic role of ApoE in degenerative brain disorders, we analysed ApoE in CSF. A significant (p < 0.001) reduction of CSF ApoE (1.5 +/- 1.2 ng ml-1) was found in AD compared with controls (5.0 +/- 2.7 ng ml-1). A less pronounced reduction was also found in frontal lobe dementia (3.1 +/- 1.5 ng ml-1; p < 0.05). These findings support the hypothesis that ApoE is involved in the pathogenesis of degenerative brain disorders such as AD. An increased reutilization of ApoE-lipid complexes in the brain, as part of a generalized repair process, may explain the low CSF ApoE in AD. Alternatively, the reduction of CSF ApoE may be caused by absorption of ApoE to senile plaques and neurofibrillary tangles.

Aged↗

PubMed1994

Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord.

Glycosphingolipids were determined in human spinal cord, cauda equina and femoral nerve of 10 subjects aged 20-70 years and in dorsal and ventral roots of four subjects aged 17-60 years. Myelin was isolated from corresponding tissue. Axons were isolated from the four specimens of dorsal and ventral roots. The concentration (mean and standard error of mean) of gangliosides in spinal cord was 0.80 +/- 0.03 mumol sialic acid/g fresh tissue, in cauda equina 0.40 +/- 0.02 mumol/g and in femoral nerve 0.23 +/- 0.01 mumol/g. In spinal cord only trace amounts of glycosphingolipids of the lacto series were found, and the ganglioside pattern differed from that in cerebral white matter by a relatively high proportion of GD3 and a low proportion of GD1a. The ganglioside patterns were almost identical in cauda equina and femoral nerve--the major ganglioside being 3'-LM1, 0.07 and 0.04 mumol/g respectively. Another ganglioside of the lacto series, 3'-HexLM1, was 25% of 3'-LM1. Peripheral nerve also contained three acidic glycosphingolipids in addition to sulfatide--LK1 and HexLK1 belonging to the glycosphingolipid lacto series and containing glucuronyl-3-sulfate instead of sialic acid, and inositolphosphoryl galactosylceramide. The dorsal (sensory) and ventral (motor) roots had the same major membrane lipid composition but the ganglioside concentration was 30% higher in sensory than motor nerve and myelin. The patterns of gangliotetraose gangliosides were, however, the same in motor and sensory myelin and axons. The ceramide composition of the gangliosides is also reported.

Adolescent↗