Biomedical subjects

J Nilsson

Publications and source records attributed to J Nilsson.

At least 91 records · Page 5Linked to original sources

PubMed2000

Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment.

OBJECTIVES: We investigated whether the effect of bezafibrate on progression of coronary atherosclerosis in the BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was related to insulin-like growth factor (IGF)-I and glucose-insulin homeostasis. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized, serial angiographic trial of a fibrate compound, demonstrated that progression of focal coronary atherosclerosis in young patients after infarction could be retarded by bezafibrate treatment. METHODS: The treatment effects on serum concentrations of IGF-I and insulin-like growth factor binding protein (IGFBP)-1, as well as on basal and postload glucose and insulin levels, were examined, and on-trial determinations were related to the angiographic outcome measurements. RESULTS: Bezafibrate treatment resulted in a significant reduction of serum IGF-I levels, both at two and five years, and on-trial serum IGF-I levels were directly related to changes in both minimal lumen diameter (r = 0.25, p < 0.05) and mean segment diameter (r = 0.29, p < 0.05). In contrast, none of the available indexes of insulin resistance (homeostasis model assessment estimate, basal and postload plasma insulin concentrations and serum IGFBP-1 levels) were related to the angiographic changes, nor were they significantly affected by bezafibrate treatment. Multiple stepwise regression analysis showed that the relation between on-trial serum IGF-I level and coronary artery disease (CAD) progression was independent of baseline angiographic score, age, body mass index, serum lipoprotein and plasma fibrinogen concentrations and measures of glucose-insulin homeostasis. CONCLUSIONS: IGF-I could be implicated in the progression of premature CAD, and a reduction of serum IGF-I concentration could account partly for the effect of bezafibrate on progression of focal coronary atherosclerosis.

Adult↗

PubMed2000

Thioredoxin prolongs survival of B-type chronic lymphocytic leukemia cells.

Thioredoxin (Trx) is a ubiquitous protein disulfide oxidoreductase with antioxidant, cytokine, and chemotactic properties. Previously, we showed that Trx, in synergy with interleukin 1 (IL-1), IL-2, IL-4, tumor necrosis factor alpha (TNF-alpha), and CD40-ligation induced S-phase entry and mitosis in normal B cells and B-type chronic lymphocytic leukemia (B-CLL) cells. The viability of B-CLL cells stimulated by these protocols is high, and it has been hypothesized that the overexpression of Bcl-2 found in B-CLL protects the cells from apoptosis in vitro and in vivo. In this study, we have analyzed the response of cells derived from 12 samples of patients with B-CLL to recombinant human Trx in spontaneous apoptosis, with special reference to the Bcl-2 expression. Long-term cultures of B-CLL clones showed significantly higher viability when supplemented with human Trx (P =.031), also exemplified with clones surviving more than 2 months. Short-term cultures of B-CLL cells exposed to 1 microg/mL of Trx for 1, 5, or 12 days maintained expression or delayed down-regulation of Bcl-2 compared with control cultures containing RPMI 1640 medium and 10% fetal calf serum only (P =.032,. 002,.026, respectively). All B-CLL cells expressed constitutive Trx at varying but low levels, in contrast to adult T-cell leukemias, which overexpress Trx, as previously reported. We found that Trx added to B-CLL cells increased in a dose-dependent fashion the release of TNF-alpha, which has been suggested to be an autocrine growth factor for these cells. In conclusion, we have found that human recombinant Trx induced TNF-alpha secretion, maintained Bcl-2, and reduced apoptosis in B-CLL cells. (Blood. 2000;95:1420-1426)

Adult↗

PubMed2000

Integrated microanalytical technology enabling rapid and automated protein identification.

Protein identification through peptide mass mapping by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has become a standard technique, used in many laboratories around the world. The traditional methodology often includes long incubations (6-24 h) and extensive manual steps. In an effort to address this, an integrated microanalytical platform has been developed for automated identification of proteins. The silicon micromachined analytical tools, i.e., the microchip immobilized enzyme reactor (mu-chip IMER), the piezoelectric microdispenser, and the high-density nanovial target plates, are the cornerstones in the system. The mu-chip IMER provides on-line enzymatic digestion of protein samples (1 microL) within 1-3 min, and the microdispenser enables subsequent on-line picoliter sample preparation in a high-density format. Interfaced to automated MALDI-TOF MS, these tools compose a highly efficient platform that can analyze 100 protein samples in 3.5 h. Kinetic studies on the microreactors are reported as well as the operation of this microanalytical platform for protein identification, wherein lysozyme, myoglobin, ribonuclease A, and cytochrome c have been identified with a high sequence coverage (50-100%).

Autoanalysis↗

PubMed2000

Capillary liquid chromatography interfaced to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using an on-line coupled piezoelectric flow-through microdispenser

A piezoelectric flow-through microdispenser interfacing capillary liquid chromatography (LC) with matrix-assisted laser desorption/ionization time-of-fight mass spectrometry (MALDI-TOF MS) was developed for the identification of biomolecules. The MALDI target plate was placed on a computer controlled high-resolution x-y stage, on to which the column effluent was deposited as discrete spots, which thereby facilitated tracing of the chromatographic separation. The entire target plate was sprayed with a homogeneous layer of alpha-cyano-4-cinnamic acid mixed with nitrocellulose by using an air-brush. Hence the tedious manual handling of a micropipetter applying matrix solution on top of each fraction collected spot was avoided. The pre-made target plates were stable for at least 3 weeks if kept in darkness at room temperature, which easily allowed re-analysis of dispensed sample spots. The integrated microsystem was characterized and optimized by means of fluidics, dispersion, operational stability and sensitivity parameters. The dispensing unit was developed specifically to match high-resolution capillary LC separations using a dispenser with an internal volume from inlet to the ejecting nozzle of 250 nl. Minimizing dead volumes was crucial in order to maintain the chromatographic resolution. The volume of the ejected droplets was of the order of 60 pl. Successful separations of seven immunoregulating peptides were made: ACTH 1-17, bradykinin, enkephalin, angiotensin III, angiotensin II, angiotensin I and ACTH 18-39. On-line sample dispensing on the target plate in combination with trace enrichment followed by automated MALDI-TOF MS identification is demonstrated, reaching a sensitivity of 100 amol.

Journal Article↗

PubMed2000

The carboxyl-terminal fragment of alpha1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes.

alpha1-Antitrypsin (AAT) serine proteinase inhibitor is found in most biological fluids, diffuses into most tissues, and is an important factor in controlling tissue damage by proteases in inflammatory diseases such as atherosclerosis. We have previously reported that the C-terminal fragment (C-36) generated during the cleavage of AAT by proteinases forms amyloid fibrils which have biological effects unrelated to precursor functions. Here we show that the C-36 fragment is present in atherosclerotic plaques, particularly within the fibrous cap at the base of the lipid core. We also found that human monocyte stimulation with C-36 fibrils led to a strong activation of both peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma) at 1, 2, and 18 h of cell culture. A parallel increase in the intracellular lipid accumulation was also observed. Furthermore, stimulation of monocytes with C-36 for 18 h led to activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation. These data for the first time demonstrate the peptide of AAT as a component of atherosclerotic plaques and as a novel activator of PPARalpha, PPARgamma, NF-kappaB, and AP-1 in cultured monocytes. Taken together, the effects of the peptide represent a new mechanism of monocyte activation that may be of importance not only in atherogenesis, but also in other inflammatory processes.

Arteriosclerosis↗

PubMed2000

7beta-hydroxycholesterol induces Ca(2+) oscillations, MAP kinase activation and apoptosis in human aortic smooth muscle cells.

In the present study, we characterize the early cytotoxic effects of 7beta-hydroxycholesterol, a major cytotoxin in oxidized LDL, in human aortic smooth muscle cells. Within a few minutes after addition, 7beta-hydroxycholesterol induced Ca(2+) oscillations with a frequency of approximately 0.3-0.4 min(-1). A few hours later, thapsigargin-sensitive Ca(2+) pools were depleted, indicating that 7beta-hydroxycholesterol perturbs intracellular Ca(2+) homeostasis. The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (but not JNK) were activated within 5 min after addition of 7beta-hydroxycholesterol. The side-chain hydroxylated oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol were more potent in inducing apoptosis than 7beta-hydroxycholesterol and cholesterol-5alpha,6alpha-epoxide, as determined by TUNEL staining. Addition of TNFalpha (10 ng/ml) and IFNgamma (20 ng/ml) enhanced the cytotoxicity of oxysterols and potentiated apoptosis. The cytokines alone were not toxic to smooth muscle cells at these concentrations. 25-Hydroxycholesterol and 7beta-hydroxycholesterol but not cholesterol inhibited protein synthesis at 4-8 h as determined by [35S]methionine incorporation assay. Morphologically, oxysterol-induced cell death was characterized by disorganization of the ER and Golgi membranes. The Ca(2+) and ERK signals preceded the ultrastructural changes induced by 7beta-hydroxycholesterol.

Aorta↗

PubMed2000

Polymeric-based perivascular delivery of a nitric oxide donor inhibits intimal thickening after balloon denudation arterial injury: role of nuclear factor-kappaB.

OBJECTIVES: To examine the effect of a polymeric-based periadventitial delivery of a nitric oxide (NO)-releasing diazeniumdiolate, spermine/NO (SPER/NO), on balloon injury-induced neointimal hyperplasia in rat ileofemoral arteries. BACKGROUND: Reduced local bioavailability and adverse side effects limit systemic administration of NO to modulate vascular response to injury. METHODS: A polylactic-polyglycolic acid polymeric matrix containing 2.5% SPER/NO (w/w) was applied around the injured arteries. Quantitative histomorphometry was performed at day 14, proliferating cell nuclear antigen (PCNA) immunohistochemistry at day 3 to assess effects on smooth muscle proliferation and electrophoretic mobility shift assay to evaluate effects on transcription factor, nuclear factor-kappaB (NF-kappaB). RESULTS: Treatment with SPER/NO reduced the intimal area (0.011 +/- 0.009 vs. 0.035 +/- 0.006 mm2 control, p < 0.01) and the intima to media ratio (0.089 +/- 0.062 vs. 0.330 +/- 0.057 control, p < 0.005). Spermine/nitric oxide produced a profound inhibition of PCNA-positive cells (>75%, p < 0.005) and significantly suppressed the injury-induced activation of NF-kappaB. Vascular cyclic guanosine monophosphate (cGMP) levels were elevated after treatment with the SPER/NO (0.28 +/- 0.03 vs. 0.17 +/- 0.02 pmol/mg tissue control, p < 0.01). The inhibitory effects on neointimal proliferation were localized to the site of application of SPER/NO and were not associated with any changes in platelet aggregation or bleeding time. Neither SPER nor polymer alone had any significant effects on any of the variables examined. CONCLUSIONS: Polymeric-based perivascular delivery of a NO donor produces a marked localized inhibition of neointimal proliferation in balloon-injured arteries. This phenomenon is associated with suppression of NF-kappaB activation and elevation of the vascular cGMP at the site of injury.

Angioplasty, Balloon↗

PubMed2000

Genetic lineages and postglacial colonization of grayling (Thymallus thymallus, Salmonidae) in Europe, as revealed by mitochondrial DNA analyses.

In stark contrast to other species within the Salmonidae family, phylogeographic information on European grayling, Thymallus thymallus, is virtually nonexistent. In this paper, we utilized mitochondrial DNA polymerase chain reaction-restriction fragment length polymorphism (mtDNA PCR-RFLP) and sequence variation to infer the postglacial dispersal routes of T. thymallus into and within northern Europe, and to locate geographically, potential evolutionarily distinct populations. Mitochondrial analyses revealed a total of 27 T. thymallus haplotypes which clustered into three distinct lineages. Average pairwise interlineage divergence was four and nine times higher than average intralineage divergence for RFLP and sequence data, respectively. Two European grayling individuals from the easternmost sample in Russia exhibited haplotypes more genetically diverged from any T. thymallus haplotype than T. arcticus haplotype, and suggested that hybridization/introgression zone of these two sister species may extend much further west than previously thought. Geographic division of the lineages was generally very clear with northern Europe comprising of two genetically differentiated areas: (i) Finland, Estonia and north-western Russia; and (ii) central Germany, Poland and western Fennoscandia. Average interpopulation divergence in North European T. thymallus was 10 times higher than that observed in a recent mtDNA study of North American T. arcticus. We conclude that (i) North European T. thymallus populations have survived dramatic Pleistocene temperature oscillations and originate from ancient eastern and central European refugia; (ii) genetic divergence of population groups within northern Europe is substantial and geographically distinct; and (iii) the remainder of Europe harbours additional differentiated assemblages that likely descend from a Danubian refugium. These findings should provide useful information for developing appropriate conservation strategies for European grayling and exemplify a case with a clear need for multinational co-operation for managing and conserving biodiversity.

Animals↗

PubMed2000

The Harrington reconstruction for advanced periacetabular metastatic destruction: good outcome in 32 patients.

We report the outcome in 32 patients operated on for advanced periacetabular metastatic destruction, where all but 2 had Harrington class III destruction. The patients were operated on using the Harrington reconstruction technique, where threaded pins and cement and a total hip replacement are used to reconstruct the acetabulum and ilium. The median survival was 11 (0-106+) months. 13 patients lived for a year or more. At follow-up after 1 year, 10 of the 13 were free of pain at rest and weight-bearing, 6 were walking with and 7 without support, and 11 lived outside a health care facility. 2 patients died within 2 weeks of surgery, both of excessive peroperative bleeding. 2 patients had dislocations, 1 developed a deep infection, and 2 patients deep vein thrombosis. There were no complications caused by erroneous pin placement or intraoperative thromboembolic incidents. There were no mechanical failures, or radiographic signs of loosening, of the pelvic components. The Harrington reconstruction technique is an effective and long-lasting method to relieve pain and restore function in patients with advanced periacetabular metastatic destruction.

Acetabulum↗

PubMed2000

Population genetic structure of brown trout (Salmo trutta L.) within a northern boreal forest stream.

Brown trout (Salmo trutta L.) population genetic structure and its temporal stability were studied within a small forest stream in central Sweden using five microsatellite loci. Both resident and migrating brown trout are present in the watershed. Tissue samples were collected from seven sections of the stream during two consecutive years. No differences were found in multilocus FST estimates between years within sections except in one case. Moreover, differences between age cohorts within sample sections were rare. The low interannual variation and the low heterogeny between cohorts is interpreted as indications of temporal stability. Pairwise multilocus FST estimates increased with increasing geographic distance, indicating isolation by distance. It is argued that the brown trout of the Färsån stream represent a population complex. The structure is probably maintained by precise natal homing and a limited, but important, amount of gene flow between closely situated sections within the stream supporting a stepping-stone model of gene flow.

Alleles↗

PubMed2000

Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression.

Activation of vascular inflammation in response to hyperlipidemia is believed to play an important role during the early stages of atherogenesis. We demonstrate here that exposure of cultured, rat aortic smooth muscle cells to low density lipoprotein (LDL) stimulated tumor necrosis factor-alpha (TNF-alpha) mRNA and protein expression. Oxidative modification of LDL resulted in a reduction of this stimulatory effect. To analyze whether a similar response also occurs in vivo, we used a recently developed model in which the effects of a rapid accumulation of human LDL in rat arteries can be studied. As previously reported, epitopes specific for human apolipoprotein B began to accumulate in the aorta within 2 to 6 hours after injection of 6 mg of human LDL. This was followed by expression of oxidized LDL-specific epitopes after 12 hours. There was no vascular expression of TNF-alpha at baseline or in phosphate-buffered saline-injected control rats. However, 24 hours after injection of native LDL, there was a marked induction of TNF-alpha mRNA and immunoreactivity in the aorta and other large arteries, whereas injection of oxidized LDL was without effect in this respect. Preincubation of LDL with the antioxidant probucol before injection markedly decreased the expression of TNF-alpha immunoreactivity. The present findings support the notion that LDL may activate arterial expression of TNF-alpha and suggest 1 possible mechanism for the inflammatory response in the early stages of atherosclerosis. The role of LDL oxidation in this process remains to be fully elucidated.

Animals↗

PubMed2000

Monoclonal antibody against vascular cell adhesion molecule-1 inhibits neointimal formation after periadventitial carotid artery injury in genetically hypercholesterolemic mice.

Vascular cell adhesion molecule (VCAM)-1 is induced in smooth muscle cells after arterial injury, in which it has been implicated in the recruitment of inflammatory cells to the site of injury. To investigate the effect of hypercholesterolemia on VCAM-1 induction after injury and the role of VCAM-1 in neointimal response to injury, we injured the carotid artery of wild-type and apolipoprotein E null (KO) mice fed normal and high cholesterol chow. We demonstrate a graded response of VCAM-1 induction as well as monocyte/macrophage infiltration by immunohistochemistry 3 days after injury that correlated with increasing circulating cholesterol levels. Three weeks after injury, KO mice fed high cholesterol chow (KO HC group) had a significantly greater neointimal formation compared with wild-type and KO mice fed normal chow (P<0.05). Inhibition of VCAM-1 function in the KO HC group by monoclonal antibody treatment significantly reduced monocyte/macrophage infiltration and neointimal formation. There was reduced alpha-actin expression in KO HC mice 7 days after injury that was partially inhibited by VCAM-1 antibody treatment. Cell migration in an in vitro injury model was partially inhibited by monoclonal VCAM-1 antibody treatment. We propose an additional role for VCAM-1 in smooth muscle cell activation and neointimal formation after injury.

Actins↗

PubMed2000

Screening for oesophageal adenocarcinoma: an evaluation of a surveillance program for columnar metaplasia of the oesophagus.

BACKGROUND: Screening patients with columnar metaplasia of the oesophagus for adenocarcinoma is controversial owing to the low cancer incidence and diverging opinions as to whether screening improves the prognosis of these patients. Our aim was to evaluate a screening program for adenocarcinoma in patients with columnar metaplasia in the oesophagus, with focus on cancer incidence and costs. METHODS: One hundred and ninety-nine patients with columnar metaplasia of the oesophagus were identified through an endoscopy database, and the original patient records were reviewed. RESULTS: The patients were followed up for 797 years in total and during this time were subjected to 1071 upper gastrointestinal endoscopies. During the screening period 5 patients presented with adenocarcinoma; thus the cancer-incidence was 1 in 159 patient-years. The cost of detecting one cancer was 294,950 SEK (US$ 37,815). However, only four of the five patients were suitable for oesophagectomy, and of these, one patient turned out to have an advanced cancer. All patients developing cancer had columnar metaplasia of the oesophagus longer than 3 cm and specialized columnar epithelium (intestinal metaplasia/Barrett oesophagus). CONCLUSIONS: Low cancer incidence, high costs, and the doubtful prognosis for the patients with identified cancer question the benefits and cost-effectiveness of cancer screening among patients with columnar metaplasia in the oesophagus.

Adenocarcinoma↗

PubMed2000

In vivo stimulation of vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element.

High plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of cardiovascular disease. There is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. Cell culture studies have shown that very low density lipoprotein (VLDL) increases the production and secretion of PAI-1 in endothelial cells and hepatocytes, suggesting a possible mechanism for this association. To determine whether VLDL stimulates PAI-1 production in vascular cells also in vivo, Sprague-Dawley rats were injected intravenously with 6 mg/kg of VLDL (derived from human subjects with type IV hyperlipidemia). Previous studies have demonstrated that this results in an accumulation of human VLDL in the aorta and other arteries followed by increased nuclear factor-kappa B (NF-kappaB) activation. Endothelial, but not smooth muscle cells, showed a basal PAI-1 mRNA and protein expression as assessed by in situ hybridization and immunohistochemistry, respectively. Six to twenty-four hours after the VLDL injection, lipoprotein particle accumulation was seen in the aortic wall, which was accompanied by increasing PAI-1 mRNA and protein expression in endothelial and smooth muscle cells. Within the rat PAI-1 promoter we identified a sequence located at -589 to -571 with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter and located adjacent to a 4-guanosine motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp -656 and -505. Electrophoretic mobility shift assays showed that VLDL increases the binding of as yet incompletely characterized factors to this response element. Taken together these observations support a direct influence of VLDL on vascular PAI-1 gene expression ill vivo. This stimulation is exerted on the level of PAI-1 gene transcription, and involves transcription factor binding to a VLDL responsive element adjacent to a 4G motif within the PAI-1 promoter.

Animals↗

PubMed1999

Characterization of the gorilla carboxyl ester lipase locus, and the appearance of the carboxyl ester lipase pseudogene during primate evolution.

In this study we report on the isolation and characterization of the gorilla carboxyl ester lipase gene, CEL, and the corresponding CEL pseudogene. We also report on the age of the CEL pseudogene. The gorilla CEL gene is 10.5kb long and comprises 11exons intervened by introns similar to the situation in man, mouse and rat. The encoded protein is 998amino acids long and includes a 23amino acid-long leader peptide. Comparison of the coding sequence, excluding exon 11, of CEL from gorilla and man reveals a 97% similarity. Exon 11, which encodes the characteristic proline rich repeats, contains 39 repeated units in gorilla compared to 16 in man. A truncated CEL pseudogene, with the same organization as that found in man, is also shown to be present in the gorilla genome. The gorilla CEL pseudogene is 4.9kb in length and consists of 5exons interrupted by introns. Southern analysis of the gorilla CEL locus shows that the locus is arranged in a similar way as in man with the functional CEL gene being the most 5' one. To bring further insight to the events involved in the rearrangement of the CEL locus, genomic Southern analyses were performed across several primates; Homo sapiens, Pan troglodytes, Gorilla gorilla, Pongo pygmaeus and Macaca arctoides. Results presented show that the CEL gene duplication occurred prior to the separation of Hominidae (man, chimpanzee, gorilla and orangutan) from Old World monkeys (macaque). The deletion of the original CEL gene giving rise to the truncated version of the CEL gene seems, however, to be restricted to man and the great apes only.

Amino Acid Sequence↗

PubMed1999

Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoE null mice.

Arterial injury triggers an inflammatory response in part mediated by induction of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and is implicated in neointimal thickening. Since HDL is known to reduce cytokine-activated VCAM-1 expression, we tested the hypothesis that VCAM-1 expression and neontimal thickening following arterial injury are inhibited by reconstituted human HDL containing plasma-derived apoA-1 (rHDL). We used the carotid cuff injury in apoE (-/-) mice fed high cholesterol. Mice received rHDL (40 mg/kg) intravenously every other day for 3 weeks. Compared to control, rHDL treatment inhibited neointima formation (0. 008 +/- 0.004 mm(2) vs. 0.037 +/- 0.019 mm(2); P < 0.01) 21 days after injury, reduced VCAM-1 expression, and decreased monocyte/macrophage infiltration as assessed by histomorphometric analysis within the first week after injury. These changes occurred without any effect on plasma total and HDL cholesterol levels as well as the arterial tissue cholesterol levels. rHDL treatment also reduced the formation of modified lipoprotein in the arterial wall compared to control within the first week after injury. This finding suggests an antioxidant effect of rHDL associated with reduced VCAM-1 expression and neointimal formation after arterial injury.

Animals↗

PubMed1999

Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells.

High plasma levels of VLDL are associated with increased risk for atherosclerosis. Here we show that VLDL (75 to 150 microg/mL) activates nuclear factor-kappaB (NF-kappaB), a transcription factor known to play a key role in regulation of inflammation. Oxidation of VLDL reduced its capacity to activate NF-kappaB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappaB to the same extent as did VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kappaB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kappaB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as the cytokine tumor necrosis factor-alpha. Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kappaB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression of NF-kappaB to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kappaB. The effect appears to be mediated by a release of VLDL fatty acids but not to involve VLDL oxidation.

Animals↗

PubMed1999

[Surgery provides symptomatic relief in skeletal metastases].

The skeleton is the third most common site of metastasis, after the lungs and the liver. Although metastasis to bone is associated with considerable morbidity, it is seldom the direct cause of death. Orthopaedic treatment of imminent or existing pathological fractures has been associated with a dismal outcome until recently, when the treatment principles of trauma surgery and arthroplasty began to be applied in cases of skeletal metastasis. The article consists in a report of 141 patients with symptoms of skeletal metastasis to the pelvis or extremities, where the indication for surgery was pathological fracture in 85 per cent of cases, the femur being the commonest site, followed by the humerus. A third of the patients had breast cancer. Median survival was six months in the series as a whole. At follow-up after one week, four months, and one year, outcome was rated as good or very good by 98, 99 and 100 per cent of the patients, respectively.

Aged↗