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Biomedical subjects

M den Heijer

Publications and source records attributed to M den Heijer.

At least 19 recordsLinked to original sources
PubMed2006

Oral anticoagulant treatment with coumarin derivatives does not influence plasma homocysteine concentration.

BACKGROUND: High circulating levels of homocysteine are a risk factor for arterial and venous thrombosis. This association has been established in numerous case-control studies. In some of these studies, patients were treated with anticoagulants at the time of venapuncture. It is not clear whether homocysteine concentrations are influenced by anticoagulants. If anticoagulation does, indeed, have an effect on homocysteine levels, it might underestimate or overestimate the possible association of homocysteine levels and vascular disease. METHODS: In this study we used two different groups to investigate the effect of coumarin derivatives on homocysteine concentrations. Homocysteine levels were measured in 40 patients who were on the waiting list for orthopedic surgery and who were expected to receive prophylactic anticoagulant therapy after the operation. Measurements were taken before the operation, as well as during and after coumarin therapy. Homocysteine concentrations were also measured in a second study group consisting of 12 healthy volunteers who were treated with oral anticoagulants. RESULTS: Mean homocysteine concentrations increased by 6% (95% CI 2-10%) during the treatment with coumarin derivatives. This corresponds to a 1 mumol/L increase in homocysteine concentration. After the anticoagulant treatment period, the concentrations decreased again. We determined that this slight increase does not influence the interpretation of epidemiological studies. We also observed no significant effect of anticoagulants on homocysteine concentration after 13 weeks of treatment of healthy volunteers (decrease of 3.6%, or approximately 0.6 micromol/L; 95% CI -17.5-8.5%). CONCLUSION: We conclude that anticoagulation does not influence homocysteine concentrations to any significant degree.

Journal Article↗
PubMed2006

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis.

Elevated plasma homocysteine concentration has been suggested as a risk factor for schizophrenia, but the results of epidemiological studies have been inconsistent. The most extensively studied genetic variant in the homocysteine metabolism is the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, resulting in reduced enzyme activity and, subsequently, in elevated homocysteine. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) was carried out to examine the association between homocysteine and schizophrenia. In addition, a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C>T polymorphism was carried out to assess if this association is causal. A 5 micromol/l higher homocysteine level was associated with a 70% (95% confidence interval, CI: 27-129) higher risk of schizophrenia. The TT genotype was associated with a 36% (95% CI: 7-72) higher risk of schizophrenia compared to the CC genotype. The performed meta-analyses showed no evidence of publication bias or excessive influence attributable to any given study. In conclusion, our study provides evidence for an association of homocysteine with schizophrenia. The elevated risk of schizophrenia associated with the homozygous genotype of the MTHFR 677C>T polymorphism provides support for causality between a disturbed homocysteine metabolism and risk of schizophrenia.

Amino Acid Substitution↗
PubMed2006

Are B vitamins a risk factor for VTE? Perhaps.

Venous thrombosis is considered as a multicausal disease. Hyperhomocysteinemia is considered as one of the risk factors for venous thrombosis. Because homocysteine levels are strongly influenced by the intake and concentrations of B vitamins, it is worthwhile to assess the role of these vitamins as a risk factor for venous thrombosis.

Homocysteine↗
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↗
PubMed2006

Transsphenoidal pituitary surgery via the endoscopic technique: results in 35 consecutive patients with Cushing's disease.

OBJECTIVE AND DESIGN: The endoscopic technique has been recently introduced in the field of transsphenoidal pituitary surgery. This technique allows inspection of sellar, supra- and parasellar structures and removal of the tumor under direct visualization, is minimally traumatic and permits easier reoperations. This is the first report on the results of endoscopic surgery for patients with Cushing's disease. Our aim was to retrospectively analyze the results of pituitary surgery in 35 consecutive patients with Cushing's disease operated in our hospital after the introduction of the endoscopic technique (1998-2004). METHODS: Remission was defined as suppression of plasma cortisol (< or =50 nmol/L) after 1 mg dexamethasone overnight determined in the first 3 months after surgery and disappearance of clinical signs and symptoms of hypercortisolism. The patients were followed for an average of 27 months (range 4 to 81 months, median 20 months). RESULTS: Pituitary MRI showed a macroadenoma in 6 patients, a microadenoma in 17 patients and no adenoma in 12 patients. After the initial surgery 27 patients (77%) were in remission. None of the patients had a relapse during follow-up. In the remaining 8 patients hypercortisolemia persisted after surgery. Three of them had a second endoscopic pituitary surgery resulting in remission in two patients. In one patient a second endoscopic pituitary surgery will soon follow. The remaining four patients were treated with radiotherapy postoperatively. Two of them were at the time of data collection in remission. One patient from the remission group had a serious epistaxis and three patients had cerebrospinal fluid leakage, one requiring an external lumbar drain, shortly after surgery. No complications were recorded in the failure group. Postoperatively 34% of all patients required substitution with levothyroxine, 40% required substitution with glucocorticoids, 17% received estrogens or testosterone and 6% still required desmopressin. CONCLUSIONS: Endoscopic transsphenoidal pituitary surgery resulted in our series of patients with Cushings disease in an excellent postoperative remission rate. A randomized clinical trial, comparing endoscopic and conventional pituitary surgery in patients with Cushings disease, is needed to determine the pros and cons of both techniques.

ACTH-Secreting Pituitary Adenoma↗
PubMed2006

Diabetes mellitus is strongly associated with tuberculosis in Indonesia.

SETTING: Diabetes mellitus is a known risk factor for tuberculosis (TB), but no studies have been reported from South-East Asia, which has a high burden of TB and a rapidly growing prevalence of diabetes. OBJECTIVE: To examine if and to what extent diabetes is associated with an increased risk of TB in an urban setting in Indonesia. DESIGN: Case-control study comparing the prevalence of diabetes mellitus (fasting blood glucose level >126 mg/dl) among newly diagnosed pulmonary TB patients and matched neighbourhood controls. RESULTS: Patients and control subjects had a similar age (median 30 years) and sex distribution (52% male), but malnutrition was more common among TB patients (median body mass index 17.7 vs. 21.5 kg/m2). HIV infection was uncommon (1.5% of patients). Diabetes mellitus was present in 60 of 454 TB patients (13.2%) and 18 of 556 (3.2%) control subjects (OR 4.7; 95%CI 2.7-8.1). Adjustment for possible confounding factors did not reduce the risk estimates. Following anti-tuberculosis treatment, hyperglycaemia reverted in a minority (3.7%) of TB patients. CONCLUSION: Diabetes mellitus is strongly associated with TB in young and non-obese subjects in an urban setting in Indonesia. This may have implications for TB control and patient care in this region.

Adult↗
PubMed2004

[Subclinical hypothyroidism; the start of a clinical trial into the usefulness of treatment with radioactive iodine].

Subclinical hyperthyroidism is defined as the presence of serum free thyroxine (T4) and triiodothyronine (T3) levels within the reference range and a reduced serum thyrotrophin (TSH) level. Evidence is accumulating that it has important clinical effects. Randomised clinical trials are needed to answer the question whether or not treatment of subclinical hyperthyroidism prevents cardiac problems, especially atrial fibrillation, and preserves bone mineral density. A randomised, Dutch multicentre trial has recently been started. Its goal is to study whether radioiodine treatment prevents the development of atrial fibrillation and prevents decreases in bone mineral density.

Atrial Fibrillation↗
PubMed2004

Subclinical hyperthyroidism: to treat or not to treat?

Subclinical hyperthyroidism may be defined as the presence of free thyroxine and tri-iodothyronine levels within the reference range and a reduced serum thyroid stimulating hormone (TSH) level. In this review the prevalence of low TSH in the population and health consequences of subclinical hyperthyroidism, for example, effects on heart and bone mass, are discussed. Guidelines for treatment are given, based on expert opinion.

Bone Density↗
PubMed2004

A clinical and cardiovascular survey of Ehlers-Danlos syndrome patients with complete deficiency of tenascin-X.

BACKGROUND: We recently described a new autosomal recessive type of Ehlers-Danlos syndrome (EDS) based on a deficiency of the extracellular matrix protein tenascin-X (TNX). TNX-deficient patients have hypermobile joints, hyperextensible skin and show easy bruising. Because of the reported cardiovascular abnormalities in other EDS types and the excessive haematoma formation after mild trauma in TNX-deficient individuals, we investigated whether cardiovascular or coagulation abnormalities occur in these patients. METHODS: We examined seven TNX-deficient patients. One of them had a mitral valve prolapse and died postoperatively after valve replacement, before the study was completed. RESULTS: Bleeding time and coagulation factors (INR, APTT, PT and fibrinogen) were all within the normal range. Ultrasonographic examination of the carotid and femoral arteries showed normal vessel wall compliance and distensibility. Echocardiography showed a slight billowing of the mitral valve in two patients from one family. All patients had normal diameters of aortic root and ascending aorta. CONCLUSION: Although the patient group is small, there are no indications of generalised cardiovascular abnormalities in this type of EDS. We would recommend echocardiography for all these patients at the first evaluation and when a cardiac murmur appears.

Echocardiography↗
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↗
PubMed2002

Chlamydia pneumoniae, systemic inflammation and the risk of venous thrombosis.

Inflammatory mediators are involved in activation of the coagulation system, and elevated plasma concentrations of IL-6 and IL-8 are associated with an increased risk of venous thrombosis. Using serologic and molecular biologic tests, we investigated in a case-control study on patients with recurrent venous thrombosis the association between Chlamydia (C) pneumoniae and venous thrombosis and we evaluated the relation between C. pneumoniae serology and the cytokines IL-6 and IL-8. The presence of C. pneumoniae antibody titers > or = 1:16 was not associated with an increased risk of venous thrombosis (odds ratio 0.8 95% CI, 0.4-1.7). Circulating C. pneumoniae-DNA was detected in only one patient and two control subjects. IgG antibody titers against C. pneumoniae were not correlated with the concentrations of IL-6 and IL-8. These results indicate that the inflammatory process shown in patients with venous thrombosis is not related to C. pneumoniae.

Adult↗
PubMed2001

Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects?

Neural tube defects (NTD) arise in the first weeks of pregnancy due to a combination of environmental and genetic factors. In mothers of children with NTD elevated homocysteine (Hcy) levels and decreased plasma folate levels were observed, which suggests a defect in the folate-dependent Hcy metabolism. Therefore, mutations in genes coding for enzymes of this metabolism could be involved in NTD. Serine hydroxymethyltransferase (SHMT) catalyzes the reversible reaction of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene THF. Two different isoforms of SHMT are known, one is present in the cytosol (cSHMT) and the other in the mitochondrion (mSHMT). Theoretically, mutated SHMT could lead to elevated Hcy levels and to an altered distribution of the different folate derivatives and might therefore become a risk factor for NTD. This study concerns the molecular genetic analysis of genes coding for both isoforms of the SHMT enzyme by single-stranded conformation polymorphism analysis. Several mutations as well as polymorphisms were found in both genes. The relevance of two variations, the 1420 C>T mutation of the cytosolic isoform and the 4-bp deletion of the mitochondrial isoform (delTCTT 1721-1724), to NTD risk was tested in a study group, which consisted of 109 NTD patients, 120 mothers of children with NTD, and 420 controls. Neither of the two polymorphisms led to an increased risk of NTD. In mothers with the 1420 CC genotype, significant increased Hcy levels are present. Also, significantly decreased red blood cell folate and plasma folate levels were present in individuals with the 1420 CC genotype. Probably, the 1420 C>T polymorphism causes a shift in distribution of the different folate derivatives. The 4-bp deletion of the mSHMT gene did not lead to altered Hcy or folate levels. So far, the results of this study provide no direct evidence for a role of defective SHMT functioning in NTD. Still, the influence of the 1420 C>T polymorphism of the cSHMT gene on the folate-related risk of NTD needs further investigation.

Adolescent↗
PubMed2001

Detection of Chlamydia pneumoniae DNA in buffy-coat samples of patients with abdominal aortic aneurysm.

Recent studies have suggested that Chlamydia pneumoniae infection is a risk factor for abdominal aortic aneurysm. This study explores the presence of Chlamydia pneumoniae DNA in buffy-coat samples of control subjects and of patients with abdominal aortic aneurysm. The seroepidemiological association between abdominal aortic aneurysm and Chlamydia pneumoniae was also investigated. Buffy-coat samples and serum specimens were obtained from 88 patients and 88 control subjects. Detection of Chlamydia pneumoniae DNA in buffy-coat samples and measurement of IgG antibodies to Chlamydia pneumoniae in serum specimens were performed by polymerase chain reaction and microimmunofluorescence, respectively. Chlamydia pneumoniae DNA was detected in buffy-coat samples of 18 (20%) patients and 8 (9%) control subjects (adjusted odds ratio 2.9, 95% confidence interval 1-8.5). IgG antibodies to Chlamydia pneumoniae were detected in 85 (97%) patients and 71 (81%) control subjects (adjusted odds ratio 7.2, 95% confidence interval 1.7-31). The results show an association between abdominal aortic aneurysm and either the presence of Chlamydia pneumoniae DNA in buffy-coat samples or IgG antibodies to Chlamydia pneumoniae. These findings support the hypothesis that previous infection with Chlamydia pneumoniae might be a risk factor for abdominal aortic aneurysm.

Adult↗
PubMed2001

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.

Adult↗
PubMed2001

A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

Alleles↗
PubMed2001

Hyperhomocysteinemia as a risk factor for venous thrombosis.

Classical homocystinuria is associated with arterial vascular diseases and venous thrombosis. In the last decade, several studies have been published indicating that even mild hyperhomocysteinemia is a risk factor for venous thrombosis. The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis. Studies on the interaction between hyperhomocysteinemia and other thrombotic risk factors are conflicting. Little is known about the pathophysiology of venous thrombosis in hyperhomocysteinemia. Several mechanisms proposed for vascular disease may be applied to venous thrombosis as well. However, up to now there is no satisfying model which might explain a thrombophilic state at plasma homocysteine concentrations in the range of mild hyperhomocysteinemia. The results of a first clinical intervention study are expected in 2002. As the results are pending, clinicians could perform homocysteine measurements in patients with venous thrombosis if screening for thrombophilia is indicated. Vitamin supplementation could be prescribed if homocysteine levels are elevated. However, the patient should be informed about the uncertainty of the benefits of vitamin supplementation.

Case-Control Studies↗
PubMed2000

Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans.

Elevated homocysteine levels have been associated with arteriosclerosis and thrombosis. Hyperhomocysteinemia is caused by altered functioning of enzymes of its metabolism due to either inherited or acquired factors. Betaine-homocysteine methyltransferase (BHMT) serves, next to methionine synthase, as a facilitator of methyl group donation for remethylation of homocysteine into methionine, and reduced functioning of BHMT could theoretically result in elevated homocysteine levels. Recently, the genomic sequence of the BHMT gene was published. Mutation analysis may reveal mutations of the BHMT gene that could lead to hyperhomocysteinemia. In the present study we performed genomic sequencing of the BHMT gene of 16 vascular patients with hyperhomocysteinemia and detected three mutations in the coding region of this gene. The first was an amino acid substitution of glycine to serine (G199S), which was found only in the heterozygous state. The second mutation was a substitution of glutamine to arginine (Q239R), and the last mutation was an amino acid substitution of glutamine to histidine (Q406H). The latter was also found only in the heterozygous state. The relevance of these mutations was tested in a study group, which consists of 190 cases with vascular disease and 601 controls. The influence of these three mutations on homocysteine levels was investigated. None of the three mutations led to significantly changed homocysteine levels. In addition, no differences in genotype distribution between cases and controls were found. So far, our results provide no evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease.

Amino Acid Substitution↗