PubMed Health⌕ Search

Biomedical subjects

P Cullen

Publications and source records attributed to P Cullen.

At least 19 recordsLinked to original sources
PubMed2006

Fatty acids in serum cholesteryl esters in relation to asthma and lung function in children.

BACKGROUND: Dietary fatty acid intake has been proposed to contribute to asthma development with n-6 polyunsaturated fatty acids (PUFA) having a detrimental and n-3 PUFA a protective effect. OBJECTIVE: The aim of our analysis was to explore the relationship between fatty acid composition of serum cholesteryl esters as marker of dietary intake and prevalence of asthma, impaired lung function and bronchial hyper-responsiveness in children. METHODS: The study population consisted of 242 girls and 284 boys aged 8-11 years, living in Munich, Germany. Data were collected by parental questionnaire, lung function measurement and skin prick test according to the International Study of Asthma and Allergies in Childhood phase II protocol. Confounder-adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association between quartiles of fatty acid concentration and health outcomes with the first quartile as reference. RESULTS: n-3 PUFA: levels of eicosapentaenoic acid were not related to asthma and impaired lung function. Linolenic acid levels were positively associated with current asthma (OR for fourth quartile 3.35, 95% CI 1.29-8.66). Forced expiratory volume in 1 s (FEV(1)) values decreased with increasing levels of linolenic acid (p for trend=0.057). n-6 PUFA: there was a strong positive association between arachidonic acid levels and current asthma (OR(4th quartile) 4.54, 1.77-11.62) and a negative association with FEV(1) (P=0.036). In contrast, linoleic acid was negatively related to current asthma (OR(4th quartile) 0.34, 0.14-0.87) and FEV(1) values increased with increasing levels of linoleic acid (P=0.022). The ratio of measured n-6 to n-3 PUFA as well as levels of palmitic and oleic acid were not consistently related to asthma or lung function. CONCLUSION: Our data do not support the hypothesis of a protective role of n-3 PUFA. Elevated arachidonic acid levels in children with asthma may be because of a disturbed balance in the metabolism of n-6 PUFA or may be secondary to inflammation in these patients.

Arachidonic Acid↗
PubMed2005

The pathogenesis of atherosclerosis.

Worldwide, more people die of the complications of atherosclerosis than of any other cause. It is not surprising, therefore, that enormous resources have been devoted to studying the pathogenesis of this condition. This article attempts to summarize present knowledge on the events that take place within the arterial wall during atherogenesis. Classical risk factors are not dealt with as they are the subjects of other parts of this book. First, we deal with the role of endothelial dysfunction and infection in initiating the atherosclerotic lesion. Then we describe the development of the lesion itself, with particular emphasis on the cell types involved and the interactions between them. The next section of the chapter deals with the events leading to thrombotic occlusion of the atherosclerotic vessel, the cause of heart attack and stroke. Finally, we describe the advantages--and limitations--of current animal models as they contribute to our understanding of atherosclerosis and its complications.

Animals↗
PubMed2005

[Use of risk factors in determining individual coronary risk].

The "Deutschland SCORE" has low predictive power and greatly overestimates the true risk of coronary heart disease in Germany. Widespread use of this score would lead to massive over-treatment. For this reason, we cannot recommend this score for general use.

Adult↗
PubMed2003

Triacylglycerol-rich lipoproteins and atherosclerosis--where is the link?

The link between raised levels of LDL (low-density lipoprotein) cholesterol in the blood and atherosclerosis is incontrovertible. The situation with regard to TRLs (triacylglycerol-rich lipoproteins) is not as clear. Nevertheless, there is substantial evidence that TRLs may in some cases be just as atherogenic as triacylglycerol-poor LDL. This review focuses on three aspects of the link between TRLs and atherosclerosis: (i) the epidemiological evidence for an association between raised levels of TRLs and atherosclerosis, with particular reference to the results of the PROCAM study; (ii) the possible pathophysiological contribution of TRL to atherogenesis at the level of the arterial wall; and (iii) the case for specific lowering of triacylglycerol levels to prevent atherosclerosis.

Arteriosclerosis↗
PubMed2003

Severe cardiac failure associated with presumed jellyfish sting. Irukandji syndrome?

We present a retrospective review of twelve cases of Irukandji syndrome associated with pulmonary oedema. This is a life-threatening envenoming due to a presumed jellyfish sting throughout Northern Australia, although only one case occurred outside North Queensland. Patients presented with significant and ongoing pain, tachycardia and hypertension. Half the patients became hypotensive requiring inotropic support. Cardiac echocardiography revealed significant cardiac dysfunction. Six patients required ventilatory support. There was no death reported due to pulmonary oedema, but one patient died of intracerebral haemorrhage. We believe patients may develop a toxin associated cardiomyopathy, and jellyfish other than Carukia barnesi may be responsible. As there is confusion with nomenclature, Carukia barnesi should be known as the Barnes jellyfish, and the diagnosis of cardiotoxic marine envenoming is suggested for any patient who has been stung by a jellyfish, develops no or minimal skin markings, and develops cardiogenic pulmonary oedema associated with Irukandji syndrome.

Adolescent↗
PubMed2002

Effects of dietary fatty acids on the composition and oxidizability of low-density lipoprotein.

OBJECTIVE: The objective of this study was to compare the effects of dietary monounsaturated fatty acids (MUFA), n-6 and n-3 polyunsaturated fatty acids (PUFA) on LDL composition and oxidizability. DESIGN, SETTING AND SUBJECTS: Sixty-nine healthy young volunteers, students at a nearby college, were included. Six subjects withdrew because of intercurrent illness and five withdrew because they were unable to comply with the dietary regimen. INTERVENTIONS: The participants received a 2-week wash-in diet rich in saturated fatty acids (SFA) followed by diets rich in refined olive oil, rapeseed oil or sunflower oil for 4 weeks. Intakes of vitamin E and other antioxidants did not differ significantly between the diets. RESULTS: At the end of the study, LDL oxidizability was lowest in the olive oil group (lag time: 72.6 min), intermediate in the rapeseed oil group (68.2 min) and highest in the sunflower oil group (60.4 min, P<0.05 for comparison of all three groups). Despite wide variations in SFA intake, the SFA content of LDL was not statistically different between the four diets (25.8-28.5% of LDL fatty acids). By contrast, the PUFA (43.5%-60.5% of LDL fatty acids) and MUFA content of LDL (13.7-29.1% of LDL fatty acids) showed a wider variability dependent on diet. CONCLUSIONS: Enrichment of LDL with MUFA reduces LDL susceptibility to oxidation. As seen on the rapeseed oil diet this effect is independent of a displacement of higher unsaturated fatty acids from LDL. Evidence from this diet also suggests that highly unsaturated n-3 fatty acids in moderate amounts do not increase LDL oxidizability when provided in the context of a diet rich in MUFA.

Adult↗
PubMed2001

The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages.

Here we report the induction of gene expression of ABCG4, a member of the ABC transporter subfamily G, from human macrophages by oxysterols and retinoids, agonists of the nuclear receptors LXR and RXR. The cloned ABCG4 transcript has a size of 3.5 kb and contains an open reading frame which encodes a polypeptide of 646 amino acids. Structurally, the putative ABC transporter protein consists of a nucleotide binding fold followed by a cluster of six transmembrane-spanning domains and thus conforms to the group of half-size ABC transporters. Among the human ABC transporter subfamily G members the novel transporter shows highest protein sequence homology and identity to ABCG1 (84 and 72%, respectively). Analysis of the genomic organization demonstrates that the ABCG4 gene is composed of at least 14 exons which extend across a region of 12.6 kb in size on chromosome 11q23.3. Based on its structural features and an LXR/RXR-responsive regulation similar to the cellular lipid export protein ABCA1, we conclude that ABCG4 may be involved in macrophage lipid homeostasis.

ATP Binding Cassette Transporter, Subfamily G↗
PubMed2001

Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells.

Sub-endothelial infiltration of monocytes occurs early in atherogenesis and is facilitated by cell adhesion molecules that are up-regulated on activated endothelium. Apolipoprotein E (apoE) helps protect against atherosclerosis, in part, because apoE particles secreted by macrophages have local beneficial effects at lesion sites. Here, we hypothesize that such protection includes anti-inflammatory actions and investigate whether cell-derived apoE can inhibit tumor necrosis factor-alpha-mediated up-regulation of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Two models were used to mimic endothelial exposure to macrophage-derived apoE. In the first, HUVECs were transiently transfected to secrete apoE; VCAM-1 induction inversely correlated with secretion of apoE into the media (r = -0.76, p < 0.001). In the second, incubation of HUVECs with media from recombinant Chinese hamster ovary (CHO) cells expressing apoE (CHO(apoE)) also reduced VCAM-1 in a dose-dependent manner (r = -0.70, p < 0.001). Characterization of CHO(apoE) cell-derived apoE revealed several similarities to apoE particles secreted by human blood monocyte-derived macrophages. The suppression of endothelial activation by apoE most likely occurs via stimulation of endothelial nitric oxide synthase; apoE increased levels of intracellular nitric oxide and its surrogate marker, cyclic guanosine monophosphate, while the nitric oxide synthase inhibitor, ethyl-isothiourea, blocked its effect. We propose that apoE secreted locally at lesion sites by macrophages may be anti-inflammatory by stimulating endothelium to release NO and suppress VCAM-1 expression.

Animals↗
PubMed2001

Expression of the ATP-binding cassette transporter gene ABCG1 (ABC8) in Tangier disease.

Several members of the ATP-binding cassette (ABC) transporter family are involved in cholesterol efflux from cells. A defect in one member, ABCA1, results in Tangier disease, a condition characterized by cholesterol accumulation in macrophages and virtual absence of mature circulating high-density lipoproteins. Expression of a second member, ABCG1, is increased by cholesterol-loading in human macrophages. We now show that ABCG1, which we identified by differential display RT-PCR in foamy macrophages, is overexpressed in macrophages from patients with Tangier disease compared to control macrophages. On examination by confocal laser scanning microscopy, ABCG1 was present in perinuclear structures within the cell. In addition, a combination of in situ hybridization and indirect immunofluorescence microscopy revealed that ABCG1 is expressed in foamy macrophages within the atherosclerotic plaque. These data indicate that not only ABCA1 but also ABCG1 may play a role in the cholesterol metabolism of macrophages in vitro and in the atherosclerotic plaque.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Apolipoprotein E in macrophages and hepatocytes is eegraded via the proteasomal pathway.

Macrophage-derived apolipoprotein E (apoE) influences the susceptibility of the arterial wall to atherosclerosis. Previous studies have shown that production of apoE in these cells is regulated at a posttranscriptional level and is increased by inhibitors of proteasomal degradation. To further investigate this mechanism, we stably transfected RAW 264.7 macrophages and HepG2 cells with a construct overexpressing ubiquitin, the peptide targeting proteins to the proteasome, fused to an influenza virus hemagglutinin epitope tag. Ubiquitination of apoE was investigated by immunoprecipitation and Western blot analysis. In both cell types, apoE was ubiquitinated, and inhibition of proteasome function by lactacystin led to accumulation of ubiquitinated apoE. These studies provide strong evidence for proteasomal degradation of apoE in the two main cell types responsible for its production and indicate a possible new level of regulation of this important protein.

Acetylcysteine↗
PubMed2001

Genomic sequence and structure of the human ABCG1 (ABC8) gene.

The human ATP-binding cassette half transporter G1 (hABCG1) may play a role in cholesterol transport in macrophages. Using RACE assays we determined the structure of this gene. The hABCG1 gene spans more than 97 kb comprising 20 exons, 20 kb and 5 exons more than hitherto described. Four of the novel exons are upstream and one is downstream of previous exon 1, and they are predicted to encode at least five novel transcripts. We also detected two separate promoters, upstream of exons 1 and 5, respectively. The region 650 bp upstream of exon 1 was predicted to contain putative binding sites for SP1 and nuclear factor kappaB (NF-kappaB), but no sterol response elements (SREs) or retinoid X receptor (RXR) binding sites. The region 650 bp upstream of exon 5 contained 19 possible SP1 binding sites, one possible SRE, two possible NF-kappaB, and two putative RXR binding sites. Nevertheless, both promoters responded in macrophages to stimulation by hydroxycholesterol and retinoic acid.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

[Obesity and cardiovascular risk].

UNLABELLED: PROBANDS AND METHOD: In the Prospective Cardiovascular Münster (PROCAM) Study, 16,288 men aged 40.5 +/- 11.3 years (mean +/- SD) and 7,328 women aged 35.8 +/- 12.3 years were enrolled between 1979 and 1991. RESULTS: Mean body mass indices (BMI) were 25.6 +/- 3.3 kg/m2 and 23.8 +/- 4.1 kg/m2 in men and women, respectively. There was a graded positive interaction in both men and women between BMI and age-standardized levels of serum total cholesterol, low density lipoprotein cholesterol, triglycerides, fasting blood glucose, uric acid, and blood pressure (both systolic and diastolic). High density lipoprotein cholesterol tended to decrease with increases in BMI in both sexes. In the subgroup of male participants aged 40-65 years without a prior history of myocardial infarction or stroke in an 8-year follow-up 258 major coronary events were observed. Although incidences of major coronary events increased with increase in relative body weight in a multiple logistic function analysis BMI did not independently contribute to cardiovascular risk, indicating that the effect of overweight on coronary heart disease is mediated via other risk factors.

Adult↗
PubMed2001

Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.

OBJECTIVES: This prospective population study was conducted to assess the role of elevated lipoprotein(a) [Lp(a)] as a coronary risk factor. BACKGROUND: The role of elevated Lp(a) as a risk factor for coronary heart disease is controversial. In addition, little attention has been paid to the interaction of Lp(a) with other risk factors. METHODS: A total of 788 male participants of the Prospective Cardiovascular Münster (PROCAM) study aged 35 to 65 years were followed for 10 years. Both Lp(a) and traditional cardiovascular risk factors (e.g., age, low density lipoprotein [LDL] cholesterol, high density lipoprotein [HDL] cholesterol, triglycerides, systolic blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family history of myocardial infarction) were evaluated in 44 men who suffered from myocardial infarction, and in 744 men who survived without major coronary events or stroke. A multiple logistic function algorithm was used to estimate global cardiovascular risk by the combined effects of traditional risk factors. RESULTS: Overall, the risk of a coronary event in men with an Lp(a) > or =0.2 g/liter was 2.7 times that of men with lower levels (95% confidence interval [CI]: 1.4 to 5.2). This increase in risk was most prominent in men with LDL cholesterol level > or =4.1 mmol/liter (relative risk [RR]: 2.6; 95% CI: 1.2 to 5.7), with HDL cholesterol < or =0.9 mmol/liter (RR 8.3; 95% CI: 2.0 to 35.5), with hypertension (RR 3.2; 95% CI: 1.4 to 7.2), or within the two highest global risk quintiles (relative risk: 2.7; 95% CI: 1.3 to 5.7). CONCLUSIONS: Lp(a) increases the coronary risk, especially in men with high LDL cholesterol, low HDL cholesterol, hypertension and/or high global cardiovascular risk.

Adult↗
PubMed2001

ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte-derived macrophages.

Apolipoprotein E (apoE) produced by macrophages in the arterial wall protects against atherosclerosis, but the regulation of its secretion by these cells is poorly understood. Here we investigated the contribution of the adenosine triphosphate binding cassette transporters ABCA1 and ABC8 to the secretion of apoE from either primary human monocyte-derived macrophages (HMDM) or human THP1 macrophages. During incubations of up to 6 h, apoE secretion from both THP1 macrophages and HMDM was stimulated by 8-Br-cAMP, which activates ABCA1 expression. The putative ABCA1 inhibitor glyburide and antisense oligonucleotides directed against ABCA1 mRNA significantly reduced apoE secretion from THP1 macrophages and HMDM. Antisense oligonucleotides directed against ABC8 mRNA also inhibited apoE secretion, although this inhibition was less pronounced and consistent than in the case of ABCA1. ApoE secretion from HMDM of ABCA1-deficient patients with Tangier disease was also decreased. ApoE mRNA expression was not affected by inhibition of ABCA1 or ABC8 in normal HMDM or the lack of functional ABCA1 in HMDM from Tangier disease patients. Inhibition of ABCA1 in HMDM prevented the occurrence of anti-apoE-immunoreactive granular structures in the plasma membrane. We conclude that ABCA1 and, to a lesser extent, ABC8 both promote secretion of apoE from human macrophages.

8-Bromo Cyclic Adenosine Monophosphate↗