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Biomedical subjects

J Nilsson

Publications and source records attributed to J Nilsson.

At least 127 records · Page 7Linked to original sources
PubMed1998

Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I(Milano)/phospholipid complex (A-I[Milano]/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I(Milano)/PC would inhibit aortic atherosclerosis in apo E-deficient mice. METHODS AND RESULTS: Thirty-five apo E-deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I(Milano)/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11 +/- 1% versus 17 +/- 5% of the aortic surface, P=.002), and lipid content increased by 45% (22 +/- 8% versus 32 +/- 6% of plaque area, P=.02) without a significant change in macrophage content (10.8 +/- 2% versus 13.2 +/- 6%). Compared with 20-week-old untreated control mice, PC only-treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11 +/- 1% versus 15 +/- 4%, P=.01) and an increase in lipid content (22 +/- 8% versus 47 +/- 3%, P<.0001) without a change in macrophage content (10.8 +/- 2% versus 11 +/- 2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I(Milano)/PC-treated mice demonstrated no increase in aortic atherosclerosis (11 +/- 1% versus 10 +/- 4%, P=NS), a 40% reduction in lipid content (22 +/- 8% versus 13 +/- 8%, P=.01), and a 46% reduction in macrophage content (10.8 +/- 2% versus 5.8 +/- 2.9%; P=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I(Milano)/PC or PC only. In vitro, apo A-I(Milano)/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I(Miano) had no effect. CONCLUSIONS: Recombinant A-I(Milano)/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E-deficient mice despite severe hypercholesterolemia. Thus, A-I(Milano)/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.

Animals↗
PubMed1998

O-GLYCBASE Version 3.0: a revised database of O-glycosylated proteins.

O-GLYCBASE is a revised database of information on glycoproteins and their O-linked glycosylation sites. Entries are compiled and revised from the literature, and from the sequence databases. Entries include information about species, sequence, glycosylation sites and glycan type and is fully cross-referenced. Compared to version 2.0 the number of entries has increased by 20%. Sequence logos displaying the acceptor specificity patterns for the GalNAc, mannose and GlcNAc transferases are shown. The O-GLYCBASE database is available through the WWW at http://www.cbs.dtu. dk/databases/OGLYCBASE/

Amino Acid Sequence↗
PubMed1998

Differences between the time constant of sensory and motor peripheral nerve fibers: further studies and considerations.

Using a method of latent addition, we previously demonstrated that sensory fibers had time constants that were about three times longer than those of motor fibers. The aim of the present work was to confirm this difference by determining the time constants for single sensory axons by using microneurography and for single motor axons by recording single motor units with bipolar concentric needle electrodes. To determine the influence of the conditioning pulse on the neural time constant, we used both depolarizing and hyperpolarizing conditioning pulses. When hyperpolarizing conditioning pulses at comparable intensity were applied, the tendency was to find shorter time constants than when depolarizing pulses were applied, although still with the motor time constant being slightly shorter. Although the absolute values varied with the different methods, the sensory time constant was generally three times the motor time constant for depolarizing conditioning stimuli, whereas for hyperpolarizing conditioning stimuli the difference dropped to about one and a half. These characteristics improve understanding of the behavior of sensory and motor axons, and, in particular, explain the differential excitability. Determination of neural time constants might prove valuable for clinical use.

Adult↗
PubMed1998

Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease.

Elevated plasma levels of triglyceride-rich lipoproteins, a decreased high-density lipoprotein (HDL) cholesterol concentration, hyperinsulinemia, and impaired fibrinolytic function frequently aggregate in patients with premature coronary heart disease (CHD). Experimental studies suggest that the cytokine tumor necrosis factor alpha (TNFalpha) produced by adipocytes plays a part in the regulation of triglyceride and glucose metabolism. The present study examined whether TNFalpha is implicated in these metabolic and fibrinolytic disturbances in young postinfarction patients. TNFalpha levels were determined in two groups of young (age <45 years) male postinfarction patients (n = 92 and 60) and in matched, population-based control subjects (n = 63). Plasma TNFalpha was higher in patients than in controls (4.1 +/- 1.6 v2.5 +/- 0.4 pg/mL, P < .0001). In hyperlipidemic patients, TNFalpha levels correlated significantly with the concentrations of very-low-density lipoprotein (VLDL) triglyceride and cholesterol and negatively with HDL cholesterol. Treatment with bezafibrate decreased VLDL triglycerides and increased HDL cholesterol, but did not affect TNFalpha levels. The TNFalpha concentration also correlated significantly with fasting glucose and proinsulin concentrations, as well as glucose and proinsulin levels after glucose ingestion. In contrast, no relations were found with the insulin level or degree of insulin resistance. The present results provide clinical evidence for a basic role of TNFalpha in hypertriglyceridemia, glucose intolerance, and the etiology of premature CHD.

Bezafibrate↗
PubMed1998

A multiway 3D QSAR analysis of a series of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxybenzamides.

Recently, the multilinear PLS algorithm was presented by Bro and later implemented as a regression method in 3D QSAR by Nilsson et al. In the present article a well-known set of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxybenzamides, with affinity towards the dopamine D2 receptor subtype, was utilised for the validation of the multilinear PLS method. After exhaustive conformational analyses on the ligands, the active analogue approach was employed to align them in their presumed pharmacologically active conformations, using (-)-piquindone as a template. Descriptors were then generated in the GRID program, and 40 calibration compounds and 18 test compounds were selected by means of a principal component analysis in the descriptor space. The final model was validated with different types of cross-validation experiments, e.g. leave-one-out, leave-three-out and leave-five-out. The cross-validated Q2 was 62% for all experiments, confirming the stability of the model. The prediction of the test set with a predicted Q2 of 62% also established the predictive ability. Finally, the conformations and the alignment of the ligands in combination with multilinear PLS, obviously, played an important role for the success of our model.

Algorithms↗
PubMed1998

Helicobacter pylori seropositivity is not associated with inflammatory parameters, lipid concentrations and degree of coronary artery disease.

OBJECTIVES: To determine the prevalence of chronic infection with Helicobacter pylori (HP) in patients with established coronary artery disease (CAD) and in healthy controls. Furthermore, to investigate whether HP infection is associated with inflammatory parameters, lipid concentrations and degree and progression of CAD. DESIGN: A case-control study combined with a prospective angiographic study. SETTING: Stockholm Metropolitan Area, Sweden. PATIENTS AND METHODS: A material consisting of 92 young men aged 40.9 +/- 3.2 (mean +/- SD) years, with previous myocardial infarction and documented coronary atherosclerosis, and 95 healthy sex-matched controls, aged 43.2 +/- 3.0 (mean +/- SD) years, with similar socio-economic status and ethnic background was analysed for the prevalence of HP seropositivity, plasma concentrations of the inflammatory parameters fibrinogen, tumour necrosis factor alpha and orosomucoid, and serum concentrations of lipids. The impact of HP seropositivity on degree and progression of CAD, as assessed by quantitative coronary angiography, was also determined. RESULTS: The study population of mainly Scandinavian origin had a low prevalence of HP seropositivity in comparison with previously published European populations. No significant increase in HP seropositivity was found in patients compared with controls (42.2 vs. 32.6%). Furthermore, HP infection was not associated with increased levels of inflammatory parameters, lipid concentrations or with degree of angiographically determined CAD at baseline, or progression of CAD and clinical events over 5 years. CONCLUSIONS: HP infection is not associated with inflammatory parameters and lipid concentrations and could not be confirmed as a risk factor for CAD.

Adult↗
PubMed1998

A RAPD-PCR method for large-scale typing of Bacillus cereus.

A robust RAPD-PCR procedure for large-scale typing of Bacillus cereus was developed. It is based on a simple DNA preparation, involving only freezing and boiling of cells in water with active carbon. By using a computerized system for data collection and processing, an efficient system for handling RAPD patterns for large-scale investigations was achieved. The procedure was highly discriminatory for Bacillus cereus strains and was found to give reproducible classification of RAPD fingerprints for five reference strains.

Animals↗
PubMed1998

Progression of coronary artery disease in young male post-infarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function.

AIMS: To assess determinants of coronary artery disease progression in men with previous myocardial infarction. METHODS AND RESULTS: A total of 102 unselected non-diabetic Swedish men (age 40.4 +/- 3.6, range 23-44 years) entered the study 3-6 months after a first myocardial infarction. The programme included metabolic and haemostatic investigations and routine coronary angiography at baseline, followed by re-angiography 5 years later. Of the original cohort, 76 patients underwent a second angiogram. Separate semiquantitative scoring systems were used for diffuse coronary atherosclerosis and distinct stenoses in 15 proximal coronary segments. Smoking, global severity of coronary atherosclerosis and presence of multi-vessel disease at baseline (P < 0.001) characterized patients with severe progression of both diffuse and focal lesions. Higher plasma levels of low density lipoprotein cholesterol (P < 0.01) and low density lipoprotein triglycerides (P < 0.05), a lower plasma high density lipoprotein2 cholesterol level (P < 0.05) and higher plasma plasminogen activator inhibitor-1 activity (P < 0.05), together with a high baseline stenosis score (P < 0.001) characterized patients with severe progression of coronary atherosclerosis. On the other hand, more pronounced fasting and post-prandial glycaemia (P < 0.05), together with higher plasma plasminogen activator inhibitor-1 activity (P < 0.01) characterized severe progressors with respect to coronary stenosis. Multivariate analysis identified the presence of multi-vessel disease as an independent predictor of progression of both coronary atherosclerosis (P = 0.008) and stenoses (P = 0.007), whereas a high low density lipoprotein triglyceride level (P < 0.01) was independently related to progression of coronary atherosclerosis and a high fasting glucose level (P = 0.02) to progression of coronary stenoses. CONCLUSION: Disturbances in carbohydrate and lipoprotein metabolism and impaired fibrinolytic function are associated with progression of coronary artery disease in young male post-infarction patients.

Adult↗
PubMed1998

Efficacy and safety of short-term itraconazole in tinea pedis: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Treatment of plantar or moccasin-type tinea pedis with conventional oral antifungal agents produces poor response rates. Itraconazole is a synthetic, broad-spectrum, orally active antifungal agent with pronounced antimycotic activity. OBJECTIVE: To confirm the efficacy and safety of short-term treatment with itraconazole for plantar or moccasin-type tinea pedis. METHODS: The study was a double-blind, randomized, placebo-controlled, multicenter trial. Seventy-two patients with tinea pedis (plantar or moccasin-type) were treated with itraconazole (200 mg twice daily) or placebo for 1 week with an 8-week treatment-free follow-up period. RESULTS: Thirty-six patients were randomized to each treatment group. The overall success rate (mycological cure and clinical response) at the end-point of follow-up was significantly higher in the itraconazole group than in the placebo group (53 vs. 3%; p <0. 001). Mycological cure (56 vs. 8%; p <0.001) and clinical response rates (75 vs. 11%; p <0.001) were significantly higher after itraconazole treatment compared with placebo treatment. During treatment, adverse events were recorded in 7 patients in the itraconazole group and 2 patients in the placebo group. Adverse events were noted in 3 patients in the placebo group during follow-up. No serious adverse events were reported in either group. CONCLUSIONS: Short-term treatment with itraconazole was significantly more effective than placebo in tinea pedis. The safety and tolerability profile or itraconazole was comparable with placebo.

Abdominal Pain↗
PubMed1998

Lipoprotein-like phospholipid particles inhibit the smooth muscle cell cytotoxicity of lysophosphatidylcholine and platelet-activating factor.

Oxidation of LDL is associated with degradation of phosphatidylcholine into platelet-activating factor (PAF)-like phospholipids and lysophosphatidylcholine (LPC). Exposure of cultured human smooth muscle cells to PAF and LPC in a concentration of 25 micromol/L was found to result in complete cell death, as assessed by the MTT cytotoxicity assay and cell counting. Addition of 50 microg/mL apolipoprotein A-I- and apolipoprotein A-I(Milano)-containing phospholipid particles completely inhibited this cytotoxicity. Phospholipid complexes alone were almost as effective, whereas free apolipoprotein A-I(Milano) and albumin were without effect, suggesting that the effect was phospholipid dependent. Experiments using [14C]LPC demonstrated that apolipoprotein A-I- and apolipoprotein A-I(Milano)-containing phospholipid particles effectively bind LPC. The results show that HDL-like phospholipid particles effectively inhibit the toxic effect of phospholipids and other lipid-soluble factors. The ability of HDL to inhibit the proinflammatory and toxic effects of phospholipids generated during oxidation of LDL may be responsible for part of the antiatherogenic properties of HDL.

Apolipoprotein A-I↗
PubMed1998

Sterol 27-hydroxylase- and apoAI/phospholipid-mediated efflux of cholesterol from cholesterol-laden macrophages: evidence for an inverse relation between the two mechanisms.

Cholesterol-laden, human monocyte-derived macrophages were found to contain 27-hydroxycholesterol in proportion to their content of cholesterol ester. In accordance with previous work with human lung alveolar macrophages, there was a significant efflux of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid from the cultured cells. The efflux of 27-hydroxycholesterol was proportional to the cellular content of this steroid. Incubation of cholesterol-laden macrophages with reconstituted discoidal complexes made from apolipoprotein A-I and phospholipids resulted in a decrease in total cellular cholesterol, an increase in the efflux of free cholesterol, and a concomitant decrease in the total production and efflux of 27-oxygenated steroids, in particular, 3beta-hydroxy-5-cholestenoic acid. Reconstituted discoidal complexes with the Milano variant of apolipoprotein A-I gave virtually identical results, whereas high density lipoprotein was less efficient. These results suggest that cultured cholesterol-laden cells can export some of their excess cholesterol in the form of 27-hydroxycholesterol, 3beta-hydroxy-5-cholestenoic acid, and free cholesterol. In the presence of exogenous cholesterol acceptors, export of free cholesterol becomes more effective, resulting in less cholesterol exported via the 27-hydroxylase pathway. The balance between the two mechanisms for removal of cholesterol from macrophages may be of importance for formation of foam cells and development of atherosclerosis.

Apolipoprotein A-I↗
PubMed1998

An animal model to study local oxidation of LDL and its biological effects in the arterial wall.

Oxidized LDL (oxLDL) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis. Mainly on the basis of cell culture studies, oxLDL has been shown to produce many biological effects that influence the atherosclerotic process. To study LDL oxidation in vivo, we have established a model in which Sprague-Dawley rats are given a single injection of unmodified human LDL (> or = 4 mg/kg body weight). Within 6 hours, an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media. The presence of oxLDL is associated with activation of the transcription factor nuclear factor-kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule-1. Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B, but the expression of oxLDL-specific epitopes was reduced at 24 hours. Thus, this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo.

Adult↗
PubMed1998

Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus.

Human obesity is associated with an increased tumor necrosis factor-alpha (TNF-alpha) mRNA expression in adipose tissue. TNF-alpha decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-alpha may play a role in insulin resistance. In this study, we analyzed plasma levels of TNF-alpha in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. Twenty of the patients had a moderate level of insulin resistance and 20 were severely insulin resistant. The plasma levels of TNF-alpha were higher in patients (4.00+/-1.53 pg/mL in moderately insulin resistant and 4.91+/-1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27+/-0.79 pg/mL, P<0.001). TNF-alpha was significantly related to body mass index, fasting glucose levels, and serum triglyceride levels and inversely related to the high density lipoprotein cholesterol level. The finding of an association between high plasma levels of TNF-alpha and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-alpha may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus.

Aged↗
PubMed1998

Role of caveolae in cholesterol transport in arterial smooth muscle cells exposed to lipoproteins in vitro and in vivo.

Arterial smooth muscle cells are able to shift between two major differentiated states with distinct morphologic and functional properties, a contractile phenotype and a synthetic phenotype. Recently, it was demonstrated that contractile smooth muscle cells have numerous caveolae and that these specialized regions of the plasma membrane, to a large extent, are lost when the cells are modified into a synthetic phenotype. At the same time, the levels of the cholesterol-binding membrane protein caveolin remained unchanged and caveolin was redistributed from the cell surface to the perinuclear cytoplasm. In the present investigation, electron microscopy was used to study how smooth muscle cells of different phenotypes react to exposure to low-density lipoprotein and other lipoproteins both in vitro and in vivo. Our findings indicate that contractile cells (present early in primary culture and in the media of normal arterial walls) do not accumulate lipids in the cytoplasm and release excess cholesterol by means of plasma membrane caveolae. Extracellularly, the expelled lipids were built into membranous configurations and piled up as myelin-like deposits. In synthetic cells (formed after a few days in primary culture and as a response to arterial injury), lipids gathered in cytoplasmic droplets and increased amounts of membranous inclusions appeared in endosomes and lysosomes. On the other hand, no signs of extracellular discharge of lipids were detected. The results suggest that contractile smooth muscle cells use caveolin and caveolae to free themselves of excess lipoprotein-derived cholesterol and so manage to maintain a balance in the influx and efflux of cholesterol. Synthetic smooth muscle cells show a Golgi-like immunostaining for caveolin but have an insufficient capacity to use this protein to transport cholesterol to the plasma membrane and out of the cell. Cholesterol will then rather be esterified and collect in lipid droplets, eventually leading to foam cell formation if the uptake of lipoprotein continues.

Animals↗
PubMed1998

Epitope dissection of receptor-active gangliosides with affinity for Helicobacter pylori and influenza virus.

Receptor-active gangliosides with affinity for Helicobacter pylori and influenza virus were chemically modified and analyzed by negative ion fast atom bombardment mass spectrometry (FAB MS) or electron ionization mass spectrometry (EI MS) after permethylation. Derivatizations included mild periodate oxidation of the sialic acid glycerol tail or conversion of the carboxyl group to primary alcohol or amides. The modified gangliosides were then tested for binding affinity using thin-layer plates overlaid with labeled microbes or microbe-derived proteins. Mild periodate oxidation, which shortens sialic acid tail without destruction of sugar cores, abolished or drastically reduced binding of H. pylori and avian influenza virus to sialyl-3-paragloboside (S-3-PG). The same effect was observed in the case of binding of the human influenza virus to receptor-active gangliosides of human leukocytes. Conversion of S-3-PG or leukocyte gangliosides to primary alcohols or amides also abolished the binding. However, mild periodate oxidation had no effect on binding of NAP (neutrophil-activating protein of H. pylori) to the active ganglioside.

Binding Sites↗
PubMed1997

Polyamines regulate both transcription and translation of the gene encoding ornithine decarboxylase antizyme in mouse.

The degradation of ornithine decarboxylase (ODC) is mediated by antizyme, a protein regulated by the end-products of ODC activity, the polyamines. High levels of polyamines induce a +1 ribosomal frameshift in the translation of the rat antizyme message leading to the expression of a full-length protein. We have studied whether the regulation of antizyme expression occurs only at the level of translation or whether polyamine levels also affect the transcription of the antizyme gene. Thus, we have cloned and sequenced the mouse homologues of the rat ODC-antizyme gene and cDNA. Northern blot analysis shows that although high concentrations of polyamines do not affect the steady-state levels of antizyme message in L1210 leukemia cells, polyamine depletion using 2-(difluoromethyl)ornithine [Orn(F2Me)] leads to a marked decrease in mRNA levels. Results of transient transfections of luciferase-reporter-gene constructs driven by antizyme promoter fragments in untreated and Orn(F2Me)-treated Balb/C 3T3 cells indicate that the transcription of the antizyme gene is altered upon polyamine depletion. The amount of antizyme protein on Western blots was also altered by polyamine depletion and addition, and the polysomal distribution of antizyme message suggests a general translational increase of the message when polyamine concentrations are high. These results indicate a role for polyamines in the transcriptional and translational regulation of ornithine decarboxylase antizyme.

Animals↗