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Biomedical subjects

J de Graaf

Publications and source records attributed to J de Graaf.

At least 19 recordsLinked to original sources
PubMed2006

Non-transferrin-bound iron is associated with plasma level of soluble intercellular adhesion molecule-1 but not with in vivo low-density lipoprotein oxidation.

BACKGROUND: Excess body iron is associated with increased cardiovascular disease risk, possibly via non-transferrin-bound iron (NTBI)-mediated enhancement of inflammation and oxidation of low-density lipoprotein (LDL). METHODS: We assessed this proposed atherosclerotic mechanism of body iron by determining the relationship of levels of serum iron parameters, including NTBI, with plasma markers of inflammation and LDL oxidation in 232 subjects who visited the outpatient clinic for hemochromatosis family screening. RESULTS: Plasma level of soluble intercellular adhesion molecule-1 (sICAM-1) was positively related to ferritin (standardized beta coefficient 0.16) and to NTBI (0.185) and negatively to total iron-binding capacity (TIBC, -0.166). Significant higher levels of sICAM-1 were found for subjects in the highest quartile of NTBI compared to the lowest quartile of NTBI (122 microg/L (107-141) and 106 microg/L (89-125), median (interquartile range), p<0.001). Odds ratio of subjects having sICAM-1 level above 134 microg/L (75th percentile) in the highest and lowest quartile of NTBI amounted 2.3. White blood cell count was positively related to ferritin (0.149). High-sensitivity C-reactive protein, interleukin-6, interleukin-8, oxidized LDL, oxidized LDL/apolipoprotein B and IgG and IgM antibodies to oxidized LDL were not related to any of the markers of iron status. CONCLUSION: Excess body iron, reflected by elevated serum ferritin and NTBI and decreased TIBC, is associated with increased plasma level of sICAM-1 but not with markers of in vivo LDL oxidation.

Adult↗
PubMed2006

The Gln223Arg polymorphism in the leptin receptor is associated with familial combined hyperlipidemia.

OBJECTIVE: Familial combined hyperlipidemia (FCH) is characterized by elevated levels of total cholesterol (TC), triglycerides (TG) and apolipoprotein B (apo B) and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have also been associated with obesity, insulin resistance and atherosclerosis. Leptin exerts its effect through the leptin receptor (LEPR). The aim of this study is to determine whether the Gln223Arg polymorphism in the LEPR gene contributes to FCH and its associated phenotypes. METHODS: The study population consists of 37 families, comprising 644 subjects, of whom 158 subjects were diagnosed as FCH. The FCH diagnosis was based on plasma TC and TG levels, adjusted for age and gender, and absolute apo B levels, according to our recently published nomogram. The Gln223Arg polymorphism was studied by restriction fragment length polymorphism-PCR. RESULTS: Carriers of one or two Arg alleles had an increased risk of FCH, compared to subjects homozygous for the Gln allele (OR=1.6 [95% CI 1.0-2.4]). A difference in high-density lipoprotein cholesterol (HDL-c) levels was present between carriers and non-carriers of an Arg allele, 1.21 vs 1.28 mmol/l, respectively (P=0.04), but no differences in obesity, insulin resistance and other lipid parameters were found. CONCLUSION: The Gln223Arg polymorphism in the LEPR gene is associated with FCH, which is supported by a significant association between HDL-c levels and the LEPR gene.

Adult↗
PubMed2006

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Apolipoproteins B↗
PubMed2006

A genome-wide linkage scan for homocysteine levels suggests three regions of interest.

BACKGROUND: An elevated plasma total homocysteine (tHcy) level is a risk factor for many clinical conditions, including vascular disease and venous thrombosis. The tHcy levels are partly determined by genetic factors. Extensive candidate gene studies have identified several genetic variants, including the MTHFR 677C>T, that influence tHcy levels, but so far only part of the genetic variation in tHcy can be explained. OBJECTIVE: In order to identify chromosomal regions that influence tHcy levels, a genome-wide linkage analysis was conducted. PATIENTS/METHODS: Our study population consisted of 13 pedigrees and 469 subjects with data on fasting plasma tHcy levels. A set of 377 markers covering the genome was genotyped in 275 subjects. The variance component linkage method (SOLAR version 2.1.3) was used for the two-point and multipoint linkage analyses. RESULTS: The heritability of the age- and sex-adjusted homocysteine levels was 44%. The multipoint linkage analysis identified one region with suggestive linkage on chromosome 16q (LOD score 1.76; nominal P = 0.0024). Weaker evidence of linkage was found for regions on chromosome 12q (LOD score 1.57; nominal P = 0.0036) and chromosome 13q (LOD score 1.52; nominal P = 0.0041). CONCLUSIONS: In our families the plasma tHcy level was highly heritable. The multipoint linkage analysis identified three regions that showed weak to suggestive linkage to tHcy levels.

Adolescent↗
PubMed2005

Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia.

OBJECTIVE: Circulating oxidized low-density lipoprotein (LDL) has been shown to be a useful marker for identifying patients with coronary heart disease (CHD) and persons at high cardiovascular risk. The effect of cholesterol-lowering therapy on plasma level of oxidized LDL is not clear. METHODS AND RESULTS: We investigated effects of cholesterol lowering by therapeutic intervention (2 years) with atorvastatin (80 mg daily) and simvastatin (40 mg daily) on circulating oxidized LDL (absolute level and in proportion to plasma apolipoprotein B) in relation to atherosclerosis progression (carotid intima-media thickness, carotid IMT) and to inflammation (high-sensitivity C-reactive protein, hsCRP) in 115 stable patients with heterozygous familial hypercholesterolemia (FH). Atorvastatin and simvastatin reduced plasma-oxidized LDL (-43 and -35%, respectively) in proportion to the decrease in plasma apolipoprotein B. Neither absolute nor relative level of oxidized LDL correlated with carotid IMT or hsCRP at baseline. Also changes in levels of circulating oxidized LDL were not related to changes in carotid IMT and hsCRP. CONCLUSIONS: In familial hypercholesterolemia-oxidized LDL carried in plasma is strongly associated with apolipoprotein B but not with inflammation nor with carotid IMT, and statin treatment does not reduce oxidized LDL relative to apolipoprotein B.

Anticholesteremic Agents↗
PubMed2005

Role of insulin resistance in familial combined hyperlipidemia.

OBJECTIVE: Insulin resistance is associated with increased triglyceride levels, low high-density lipoprotein cholesterol, small dense low-density lipoprotein (LDL), and increased apolipoprotein B (apoB) levels, all characteristics of familial combined hyperlipidemia (FCH). Therefore, we explored the role of insulin resistance in FCH lipid phenotype expression. METHODS AND RESULTS: FCH was defined by traditional diagnostic criteria including plasma total cholesterol or triglyceride levels >90th percentile. Insulin resistance was assessed by the Homeostasis Model Assessment (HOMA) index. In total, 132 subjects with FCH, 350 normolipidemic relatives, and 81 spouses who referenced as controls were studied. FCH subjects were significantly more insulin resistant compared with controls and normolipidemic relatives (HOMA index 2.9 [95% CI, 2.6 to 3.2], 2.2 [95% CI, 2.0 to 2.5], and 2.0 [95% CI, 1.9 to 2.2], respectively), even after correction for sex, age, and body mass index (BMI). The degree of insulin resistance was associated with the lipid phenotype expression, and a change in insulin-resistant state was associated with a change in lipid phenotype expression over 5 years. For any level of insulin resistance and degree of obesity, FCH subjects had increased levels of apoB and more small dense LDL compared with controls. CONCLUSIONS: Insulin resistance is a characteristic feature of FCH, which is not fully explained by their increased BMI and is associated with (change in) lipid phenotype expression. Furthermore, our results support the concept of genetic origin of high apoB and small dense LDL in FCH, which is modulated by insulin resistance and obesity.

Adult↗
PubMed2005

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.

BACKGROUND: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. METHODS: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. RESULTS: Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). CONCLUSION: Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Blood Glucose↗
PubMed2005

The effect of statin therapy on plasma high-density lipoprotein cholesterol levels is modified by paraoxonase-1 in patients with familial hypercholesterolaemia.

OBJECTIVES: Statins reduce low-density lipoprotein cholesterol (LDL-C) and can raise high-density lipoprotein cholesterol (HDL-C). HDL-bound paraoxonase-1 (PON1) is associated with variations in plasma HDL-C, and may, therefore, contribute to changes of HDL-C during statin therapy. DESIGN: The effects of baseline PON1 status to HDL-C changes because of statin therapy were investigated. PON1 status was determined with (i) PON1 -107C>T and 192Q>R genotype, (ii) PON1 levels and (iii) PON1 paraoxonase, diazoxonase and arylesterase activity. SETTING: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. SUBJECTS: A total of 134 familial hypercholesterolaemia (FH) patients undergoing atorvastatin or simvastatin therapy. RESULTS: PON1 levels and activities significantly modified the HDL-C increment (P=0.002 for PON1 levels and arylesterase activity and P=0.001 for diazoxonase activity). The effects were even more evident amongst subgroup classifications based on PON1 status and baseline HDL-C concentrations: the HDL-C increment was more pronounced in subgroups of -107CT/TT or 192QR/RR genotype combined with low baseline HDL-C (+13.9%, P<0.001, respectively+15.4%, P<0.001). In contrast, the -107CC or 192QQ genotype in combination with high baseline HDL-C, did not show a significant increase of HDL-C. CONCLUSIONS: PON1 status in conjunction with baseline HDL-C levels predicts HDL-C increment during statin therapy in FH patients.

Anticholesteremic Agents↗
PubMed2004

Who does become an internist?

Internal medicine is a broad medical speciality and choosing the residency programme opens up a variety of career tracks. Despite this broad choice of subspecialities, we found that within our residency programme for internal medicine in the Nijmegen region between 1981 and 2000, 29% of the residents did not become internists but switched to other medical specialities. To further complicate the efficiency of the residency programme, about 20% of the residents who became internists did not finish within six years, but had a delay of two years due to combined internal medicine/PhD tracks (the training for internist/clinical investigator). In another 20% there is a delay of six to 12 months due to part-time training tracks as well as to (multiple) pregnancies of female residents and parental leave of both sexes. Our data imply that nationwide data are urgently needed to re-evaluate the manpower planning for internal medicine by taking into consideration not only the number of residents starting in the residency programme but also to include the number of residents who actually do become internists.

Career Choice↗
PubMed2004

[Treatment of snoring and sleep apnea. Maxillo-mandibular advancement osteotomy].

In this article, a patient is presented who was treated by a maxillo-mandibular advancement osteotomy, in order to increase the volume of the oropharynx as a final treatment of the obstructive sleep apnea syndrome. This syndrome is a common affliction, characterized by excessive daytime sleepiness and unintentionally falling asleep. It can be diagnosed by patient history and polysomnography. Nasal-continuous positive airway pressure is the golden standard of treatment. However, in mild to moderate cases of the syndrome, treatment with a mandibular reposition appliance is also an option. The extraoral device of the first treatment option as well as the intraoral appliance of the second treatment option are demanding patients' compliance. Therefore, research into other treatments is necessary. The initial results of the advancement osteotomy among six patients were very good and in accordance with other literature reports. These results justify further research to clarify the importance of this treatment option of the obstructive sleep apnea syndrome.

Humans↗
PubMed2003

Plasma homocysteine in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia and/or hypertriglyceridemia and associated with an increased risk of cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects with FCH are relatively moderately elevated and do not fully explain the increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine metabolism and also a well-known independent risk factor for CVD. We investigated whether subjects with FCH have higher plasma homocysteine concentrations than controls, and whether homocysteine contributes to the increased risk of CVD in FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein metabolism and/or insulin resistance are associated with the homocysteine level. In total 667 subjects, including 161 subjects with FCH, 109 spouses who referenced as control group and 397 normolipidemic relatives were studied. FCH was defined by the presence of plasma total cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. The mean homocysteine concentration of the FCH group did not significantly differ from the control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH was not higher than in subjects without FCH. No associations were observed between plasma homocysteine concentration and plasma lipid and lipoprotein levels, including small dense low density lipoprotein, nor between homocysteine concentration and insulin resistance.

Adult↗
PubMed2003

Geriatric syndromes: medical misnomer or progress in geriatrics?

Both in geriatric and internal medicine journals, and in medical textbooks certain (aggregates of) symptoms are labelled as 'geriatric syndromes'. In frail elderly patients a large number of diseases present with well-known and highly prevalent atypical symptoms (e.g. immobility, instability, impaired cognition and incontinence), which are referred to as geriatric syndromes. While classically the term syndrome is used for grouping together multiple symptoms with a single pathogenetic pathway, geriatric syndrome primarily refers to one symptom or a complex of symptoms with high prevalence in geriatrics, resulting from multiple diseases and multiple risk factors. The geriatric workup should therefore consist of both a search for and treatment of the aetiologically related diseases and a risk factor assessment and reduction. Effectiveness and efficiency of this specific geriatric syndrome workup has been demonstrated predominantly for combinations of geriatric syndromes that often serve as targeting criteria for geriatric interventions, and for some specific geriatric syndromes. Therefore, we argue that the concept of geriatric syndromes is valuable as a theoretical frame, a directive for diagnostic analysis and as an educational tool in teaching geriatrics to medical students and trainees. Added to this, explaining the heterogeneous way 'syndrome' is used in current clinical practice, as opposed to 'disease', will also substantially improve clinical reasoning both in geriatrics and general internal medicine.

Aged↗
PubMed2001

Effects of alpha-tocopherol on superoxide production and plasma intercellular adhesion molecule-1 and antibodies to oxidized LDL in chronic smokers.

Antioxidants have been postulated to exert beneficial effects in atherosclerosis. Atherosclerosis is associated with raised plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and autoantibodies against oxidized low-density lipoprotein (oxLDL). It is not known whether antioxidants affect these plasma factors in chronic smokers. In a randomized double-blind placebo-controlled study involving 128 male normolipidemic chronic smokers the effect of a 2-year alpha-tocopherol treatment (400 IU dL-alpha-tocopherol daily) on plasma levels of sICAM-1 and autoantibodies against oxLDL was evaluated. In addition, we monitored production of superoxide by leukocytes ex vivo. It was found that compared to nonsmokers (n = 33) plasma levels of IgG but not IgM autoantibodies against oxLDL and concentrations of sICAM-1 in smokers were significantly elevated (30 and 42%, respectively). After supplementation with alpha-tocopherol concentration of TBARS in plasma and in vitro oxidizability of LDL had decreased, but autoantibodies and sICAM-1 had not changed. Production of superoxide was not different between alpha-tocopherol- and placebo-treated smokers. It is concluded that in chronic smokers, long-term treatment with alpha-tocopherol does not normalize the raised levels of sICAM-1 and autoantibodies against oxLDL, both risk factors for initiation or progression of cardiovascular disease, despite a decrease in in vitro oxidizability of LDL.

Aged↗
PubMed2000

Familial chylomicronemia caused by a novel type of mutation in the APOE-CI-CIV-CII gene cluster encompassing both the APOCII gene and the first APOCIV gene mutation: APOCII-CIV(Nijmegen).

Apolipoprotein CII (ApoCII) deficiency is a relatively rare cause of the chylomicronemia syndrome, a disorder characterized by severe fasting hypertriglyceridemia and massive accumulation of chylomicrons in plasma. Here we present a case which is the first example of apoCII deficiency caused by a major rearrangement in the APOCII gene. Southern blot analysis revealed an approximately 7.5-kb deletion disrupting the APOCII gene including the promotor region and first exon. Interestingly, the deletion also encompasses the APOCIV gene, a recently discovered novel gene upstream of APOCII. This deletion is the first mutation to be reported in the APOCIV gene.

Apolipoproteins C↗
PubMed2000

A functional NF-kappaB binding site in the human papillomavirus type 16 long control region.

By computer search, we identified one potential NF-kappaB binding site in the HPV16 long control region (LCR) at position 7554-7563 having two mismatches in comparison to the consensus NF-kappaB binding site of the Igkappa L promoter. Bandshift experiments with nuclear extracts from HeLa cells or purified glutathione S-transferase-p65 fusion protein clearly demonstrated that NF-kappaB is able to bind to this region of the LCR. However, in comparison to NF-kappaB binding on a consensus probe, the affinity of NF-kappaB for this site is about 250-fold reduced. When mutations were introduced into this NF-kappaB binding site, the activity of the LCR was increased, strongly suggesting that NF-kappaB was acting as a transcriptional repressor in the context of the HPV16 LCR. In addition, overexpression of NF-kappaB p65 repressed the activity of the HPV16 LCR, strengthening this conclusion.

Base Sequence↗
PubMed2000

[Use of margarine fortified with phytosterols as a therapeutic food].

The intake of one tub of margarine with added phytosterols per week has been shown to reduce plasma total and low density lipoprotein (LDL) cholesterol levels by 9 and 13% respectively, with no effect on high density lipoprotein (HDL) cholesterol or triglyceride levels. This reduction in cholesterol concentration may help to decrease the risk of coronary heart disease by 20 to 50%. No significant side effects have been reported. Phytosterols reduce cholesterol levels by inhibition of cholesterol absorption in the intestine. The margarines with added phytosterols are an example of functional foods (novel foods) which are designed to enhance health or contribute to reduction in a specific disease risk. In 1997, the European Union has introduced rules for the evaluation of novel foods, the Novel Food Regulatory Approval Procedure. Post-marketing surveillance of functional foods is obligatory to control long term safety and efficacy.

Cholesterol, HDL↗