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Biomedical subjects

M den Heijer

Publications and source records attributed to M den Heijer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.

OBJECTIVE: To quantify the risk of recurrent early pregnancy loss in the presence of elevated fasting or afterload homocysteine concentrations or homozygosity for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (T/T genotype). DESIGN: Case-control studies published between January 1992 and November 1999 were identified with a MEDLINE-search. These studies were combined with a recent case-control study performed by our own research group. SETTING: Academic research environment. PATIENT(S): Studies published in the English language, concerning two or more pregnancy losses before 16 weeks' menstrual age were included. INTERVENTION(S): Meta-analysis of all of the studies included. MAIN OUTCOME MEASURE(S): The number of subjects with and without hyperhomocysteinemia or with the T/T genotype were derived, if necessary the study was supplemented by personal communication with the original authors. RESULT(S): Pooled risk estimates of 2.7 (1.4 to 5.2) and 4.2 (2.0 to 8.8) were calculated for fasting and afterload plasma homocysteine concentrations, respectively. For the MTHFR T/T genotype a pooled risk estimate of 1.4 (1.0 to 2.0) was found. CONCLUSION(S): These data support hyperhomocysteinemia as a risk factor for recurrent early pregnancy loss. Further research should be focused on the pathophysiology of this relationship and on the clinical efficacy of B vitamin supplementation.

Abortion, Habitual↗
PubMed2000

Homocysteine and folate levels as risk factors for recurrent early pregnancy loss.

OBJECTIVE: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations. METHODS: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5'-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls. RESULTS: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 micromol/L and afterload greater than 61.5 micromol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1. 2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12. 8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations. CONCLUSION: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.

Abortion, Habitual↗
PubMed2000

Thrombosis prophylaxis in hospitalised medical patients: does prophylaxis in all patients make sense?

BACKGROUND: Most studies on thrombosis prophylaxis focus on postoperative venous thrombosis. In medical wards thrombosis prophylaxis is generally restricted to patients who are immobilised. Our primary aim was to investigate the incidence of venous thrombosis in a general internal ward, to assess whether more rigorous prophylaxis would be feasible. METHODS: We investigated the incidence of venous thrombosis in patients hospitalised from 1992 to 1996 and related our findings to literature reports. RESULTS: The incidence of symptomatic venous thrombosis in internal patients during hospitalisation was 39/6332 (0.6%). Among these 39 patients, 24 had a malignancy, whereas 876 out of all 6332 patients had a known malignancy. So, the incidence in this group with cancer was 2.7% compared with 0.3% (15/5456) in the non-cancer group (relative risk for venous thrombosis due to malignancy was 10.0 (95%C.I. 5.3-18.9). CONCLUSION: The incidence of venous thrombosis during hospitalisation in a department of general internal medicine is low and does not justify prophylaxis in all internal patients. Cancer is a strong risk factor for hospital-acquired thrombosis in the medical ward. Further studies may answer the question as to whether thrombosis prophylaxis in this subgroup is feasible.

Adolescent↗
PubMed2000

Homocysteine and venous thrombosis: outline of a vitamin intervention trial.

In the past years several case-control studies established the association of an elevated plasma homocysteine concentration and the risk of venous thromboembolism. It is still unclear if elevated homocysteine concentrations can cause venous thrombosis. The VITRO (VItamins and ThROmbosis) trial is the first multicenter, randomized, double-blind and placebo-controlled study to evaluate the effect of homocysteine-lowering therapy by means of 5 mg folic acid, 0.4 mg vitamin B12 and 50 mg vitamin B6. The study is a secondary prevention trial in 600 patients who suffered from a first episode of idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. There will be 300 hyperhomocysteinemic and 300 normohomocysteinemic patients included, all with an objectivated venous thrombosis. The end point is recurrence of venous thrombosis.

Adult↗
PubMed2000

Recurrent venous thrombosis and markers of inflammation.

Inflammatory processes may play a key role in venous thrombosis, by inducing a procoagulant state through the action of cytokines and chemokines on monocytes and endothelial cells. Plasma concentrations of three inflammatory mediators, interleukin 6 (IL-6), interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1), that mediate the cross-talk between inflammation and coagulation, were measured in 182 subjects with recurrent venous thrombosis and 350 healthy subjects recruited through a general practice. Elevated levels of IL-6 (>90th percentile of the control group) were detected in 25.8% of the patients with venous thrombosis in comparison with 10% (by definition) of the controls [odds ratio 2.4 (95%CI 1.5-3.8)]. In 21.5% of the patients elevated plasma levels of IL-8 (>90th percentile) were determined [odds ratio 2.0 (95%CI 1.2-3.5)]. Elevated levels of MCP-1 (>90th percentile) were detected in 24.1% of the patients [odds ratio 1.9 (95%CI 1.2-3.2)]. This is the first large clinical study showing that an increase in inflammatory mediators is associated with venous thrombosis. Future prospective studies are necessary to clarify the causal nature of the inflammatory process with respect to venous thrombosis.

Adult↗
PubMed1999

Hyperhomocysteinemia: a risk factor for ischemic stroke in children.

BACKGROUND: Moderate hyperhomocysteinemia is a risk factor for arterial vascular disease and venous thrombosis in adults. We performed a case-control study to assess a possible relation between moderate hyperhomocysteinemia and ischemic stroke in Dutch children (age range, 0 to 18 years). METHODS AND RESULTS: We measured plasma total homocysteine levels (tHcy) in 45 patients with ischemic stroke and in 234 controls. Hyperhomocysteinemia was defined as a tHcy above the 95th percentile regression line for the respective age of the controls. Hyperhomocysteinemia was present in 8 (18%) of the 45 patients with ischemic stroke. The odds ratio was 4.4 (95% CI, 1.7 to 11.6). CONCLUSIONS: We conclude that moderate hyperhomocysteinemia is a risk factor for ischemic stroke in children.

Adolescent↗
PubMed1999

[Hyperhomocysteinemia as a risk factor for venous thrombosis].

In recent years research was done to elucidate the relation between an increased homocysteine concentration and arterial as well as venous thrombosis. Several case control studies showed that an elevated homocysteine concentration is an independent risk factor for primary and secondary venous thromboembolism. It is not clear whether lowering homocysteine levels by administration of folic acid, whether or not in combination with vitamin B12 and vitamin B6, decreases the risk of vascular events. Randomized secondary prevention trials are being conducted at this moment. It is recommended to await the results of these trials before screening for and treating of individuals with hyperhomocysteinaemia.

Adult↗
PubMed1998

Hyperhomocysteinemia and venous thrombosis.

In recent years hyperhomocysteinemia has been established as a new risk factor for neural tube defects, arterial cardiovascular disease, and venous thrombosis. Concerning vascular problems, it first became clear that hyperhomocysteinemia might be (though not proven) a risk factor for arterial disease as observed in case-control studies, as well as in prospective analysis. More recently, the subject of hyperhomocysteinemia and venous thrombosis has received much attention. In this article, we discuss the issue of hyperhomocysteinemia, in general, the known causes of hyperhomocysteinemia and the association with venous thrombosis. Special attention is given to the value of the methionine loading test to diagnose hyperhomocysteinemia. An association of venous thrombosis and hyperhomocysteinemia has now been documented in several case control studies, but only in one prospective analysis. Thus far, there is limited evidence for a causal relationship for mild hyperhomocysteinemia in venous thrombosis. Briefly, the possible mechanisms of how hyperhomocysteinemia can lead to venous thrombosis are discussed. The article ends with therapeutic options to treat hyperhomocysteinemia (hyperhomocysteinemia can easily be treated with vitamins) and the description of a study that is presently being undertaken in an international multicenter design. This placebo-controlled study might resolve the question of whether lowering of homocysteine levels is of any clinical relevance in preventing recurrent venous thrombosis.

Case-Control Studies↗
PubMed1998

Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers.

Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis and is inversely related to plasma folate and vitamin B12 levels. We assessed the effects of vitamin supplementation on plasma homocysteine levels in 89 patients with a history of recurrent venous thrombosis and 227 healthy volunteers. Patients and hyperhomocysteinemic (homocysteine level >16 micromol/L) volunteers were randomized to placebo or high-dose multivitamin supplements containing 5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine. A subgroup of volunteers without hyperhomocysteinemia was also randomized into three additional regimens of 5 mg folic acid, 0.5 mg folic acid, or 0.4 mg hydroxycobalamin. Before and after the intervention period, blood samples were taken for measurements of homocysteine, folate, cobalamin, and pyridoxal-5'-phosphate levels. Supplementation with high-dose multivitamin preparations normalized plasma homocysteine levels (< or = 16 micromol/L) in 26 of 30 individuals compared with 7 of 30 in the placebo group. Also in normohomocysteinemic subjects, multivitamin supplementation strongly reduced homocysteine levels (median reduction, 30%; range, -22% to 55%). In this subgroup the effect of folic acid alone was similar to that of multivitamin: median reduction, 26%; range, -2% to 52% for 5 mg folic acid and 25%; range, -54% to 40% for 0.5 mg folic acid. Cobalamin supplementation had only a slight effect on homocysteine lowering (median reduction, 10%; range, -21% to 41%). Our study shows that combined vitamin supplementation reduces homocysteine levels effectively in patients with venous thrombosis and in healthy volunteers, either with or without hyperhomocysteinemia. Even supplementation with 0.5 mg of folic acid led to a substantial reduction of blood homocysteine levels.

Adult↗
PubMed1998

Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis.

Mild hyperhomocysteinemia is an established risk factor for both arteriosclerosis and thrombosis, and may be caused by genetic and environmental factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the cofactor for the methylation of homocysteine to methionine. Individuals with the thermolabile variant of MTHFR have decreased MTHFR activities, resulting in elevated plasma homocysteine concentrations. A homozygous 677C-->T transition in the MTHFR gene has recently been identified as the cause of reduced enzyme activity and thermolability of the protein. We studied the frequency of the homozygous mutant (+/+) genotype in 471 patients with deep-vein thrombosis and 474 healthy controls enrolled in The Leiden Thrombophilia Study (LETS), its interaction with factor V Leiden, and assessed the association between the MTHFR genotypes and plasma homocysteine concentration. Homozygosity for the 677C-->T polymorphism was observed in 47 (10%) patients, and in 47 (9.9%) controls (OR 1.01 [95% CI: 0.7-1.5]). No modified risk of the (+/+) genotype was observed in carriers of factor V Leiden. Our data suggest that, although the homozygous mutant genotype is associated with elevated plasma homocysteine concentrations, this homozygous mutation itself is not a genetic risk factor for deep-vein thrombosis, irrespective of factor V Leiden genotype.

Adolescent↗
PubMed1998

Hyperhomocysteinemia and venous thrombosis: a meta-analysis.

Hyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease. Until the early nineties the relationship with venous thrombosis was controversial. At this moment ten case-control studies on venous thrombosis are published. We performed a metaanalysis of these reports. We performed a MEDLINE-search from 1984 through June 1997 on the keywords "homocysteine" or "hyperhomocysteinemia" and "venous thrombosis", which yielded ten eligible case-control studies. We found a pooled estimate of the odds ratio of 2.5 (95% CI 1.8-3.5) for a fasting plasma homocysteine concentration above the 95th percentile or mean plus two standard deviations calculated from the distribution of the respective control groups. For the post-methionine increase in homocysteine concentration we found a pooled estimate of 2.6 (95% CI 1.6-4.4). These data from case-control studies support hyperhomocysteinemia as a risk factor for venous thrombosis. Further research should focus on the pathophysiology of this relationship and on the clinical effects of reducing homocysteine levels by vitamin supplementation.

Adult↗
PubMed1996

Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.

BACKGROUND: Previous studies have suggested that hyperhomocysteinemia may be a risk factor for venous thrombosis. To assess the risk of venous thrombosis associated with hyperhomocysteinemia, we studied plasma homocysteine levels in patients with a first episode of deep-vein thrombosis and in normal control subjects. METHODS: We measured plasma homocysteine levels in 269 patients with a first, objectively diagnosed episode of deep-vein thrombosis and in 269 healthy controls matched to the patients according to age and sex. Hyperhomocysteinemia was defined as a plasma homocysteine level above the 95th percentile in the control group (18.5 micromol per liter). RESULTS: Of the 269 patients, 28 (10 percent) had plasma homocysteine levels above the 95th percentile for the controls, as compared with 13 of the controls (matched odds ratio, 2.5; 95 percent confidence interval, 1.2 to 5.2). The association between elevated homocysteine levels and venous thrombosis was stronger among women than among men and increased with age. The exclusion of subjects with other established risk factors for thrombosis (e.g., a deficiency of protein C, protein S, or antithrombin; resistance to activated protein C; pregnancy or recent childbirth; or oral-contraceptive use) did not materially affect the risk estimates. CONCLUSIONS: High plasma homocysteine levels are a risk factor for deep-vein thrombosis in the general population.

Adolescent↗
PubMed1996

Variability of the methionine loading test: no effect of a low protein diet.

The methionine loading test is used for the diagnosis of impaired methionine/homocysteine metabolism, in particular the transsulfuration pathway. Usually this test is performed on a low protein diet to control the intake of methionine. However, this is inconvenient and relatively expensive. In this study we compared the effects of a low protein diet and a standard diet on methionine loading test in 28 subjects (crossover design). The mean difference in homocysteine concentration after methionine loading between the two diets was 1.3 [confidence interval (CI) 95%-1.0-3.6] mumol/L which demonstrates that a special low protein diet is not essential in the performance of the methionine loading test. We also observed that 3 weeks after the first methionine loading test, fasting serum concentration of folate was higher and vitamin B12 concentration was lower.

Adult↗
PubMed1996

Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T-->C (I278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-->T mutation in the MTHFR gene was found in (15%) of 60 cardiovascular patients and in only 6 (approximately 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease.

Alleles↗
PubMed1995

Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?

Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3.1 [1.8-5.5]). After adjustment for age, sex, and menopausal status the odds ratio was 2.0 (1.5-2.7). Similar results were found for the post-methionine value (unadjusted odds ratio 3.1 [1.7-5.5], adjusted 2.6 [1.9-3.5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.

Adult↗
PubMed1995

Detecting psychiatric disorders in medical practice using the General Health Questionnaire. Why do cut-off scores vary?

In this study we assessed the accuracy of the General Health Questionnaire in detecting psychiatric disorders in general medical out-patients. A total of 290 newly referred patients were interviewed with the Present State Examination. Prior to the interview, 112 patients completed the full GHQ-60, 100 completed the GHQ-30 and 78 completed the GHQ-12. Data from the first group were used to study the full GHQ-60, together with the GHQ-30 and and GHQ-12, when disembedded from the full questionnaire. In a comparison between the disembedded and the separate versions of the GHQ-30 and GHQ-12 we observed considerable variation in the cut-off scores where a certain sensitivity and specificity was attained. In ROC-analysis, the versions were not materially different in their discriminatory capacity (area under the curve). The use of different criteria to define a 'case' demonstrated that case severity was another source of increasing cut-off scores. Our data demonstrate that the use of disembedded or separate versions of the questionnaire, together with variation in the case criteria can be a major explanation for variation in cut-off scores that was observed in previous studies.

Adolescent↗