Biomedical subjects

Yvo M Smulders

Publications and source records attributed to Yvo M Smulders.

13 recordsLinked to original sources

PubMed2006

Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms.

Microalbuminuria is a strong and independent indicator of increased cardiovascular risk among individuals with and without diabetes. Therefore, microalbuminuria can be used for stratification of risk for cardiovascular disease. Once microalbuminuria is present, cardiovascular risk factor reduction should be more "aggressive." The nature of the link between microalbuminuria and cardiovascular risk, however, remains poorly understood. There is no strong evidence that microalbuminuria causes atherothrombosis or that atherothrombosis causes microalbuminuria. Many studies have tested the hypothesis that a common risk factor underlies the association between microalbuminuria and cardiovascular disease but, again, have found no strong evidence in favor of this contention. At present, the most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease, but more and prospective studies of these hypotheses are needed.

Albuminuria↗

PubMed2006

Cardiac output measurement by pulse dye densitometry: comparison with pulmonary artery thermodilution in post-cardiac surgery patients.

OBJECTIVE: Pulse-dye densitometry (PDD) could be a suitable, low-invasive alternative to thermodilution using a pulmonary artery catheter (PAC) for monitoring cardiac output. The aim of our study was to assess the reproducibility and validity of PDD compared to PAC-thermodilution. METHODS: In 43 post-cardiac surgery patients, the mean of triplicate readings of cardiac output was assessed using both methods. In a subgroup of 26 patients, a second set of measurements was obtained on average 2 h later. RESULTS: Reproducibility of consecutive measurements was slightly better for PAC-thermodilution than for PDD (median coefficient of variation of the triplicate measurements: 3.5% versus 5.4%, P < 0.01). Both methods correlated well (r = 0.84, p < 0.001). Using Bland and Altman analyses with PAC-thermodilution as the reference method, PDD showed a bias of -0.68 +/- 0.82 L/min, mainly due to differences in higher ranges of cardiac output (>6.5 L/min). Measured changes in cardiac output were 81% concordant (i.e. <1 L/min different) between both methods. CONCLUSION: PDD correlates well with PAC-thermodilution and thus deserves consideration as a low-invasive alternative for measurement and follow-up of cardiac output.

Aged↗

PubMed2006

The clinical usefulness of glucose tolerance testing in gestational diabetes to predict early postpartum diabetes mellitus.

We examined the clinical usefulness of antepartum clinical characteristics, along with measures of glucose tolerance, in Dutch multiethnic women with gestational diabetes mellitus (GDM) for their ability to predict type 2 diabetes within 6 months of delivery (early postpartum diabetes). The present study comprised a cross-sectional 5-year investigation (1998-2003) of a consecutive series of 168 women with GDM identified by a two-stage protocol at 16-33 weeks of gestation. The following data were collected for all women: age and gestational age at entry into the study; prepregnancy body mass index (BMI); ethnicity; obstetric and clinical history, including the onset of early postpartum diabetes; pregnancy outcome; level of fasting C-peptide; and glycemic parameters of 50-g 1-h glucose challenge test and 100-g 3-h oral glucose tolerance test (diagnostic OGTT). We used receiver operating characteristic (ROC) curve analysis to test the clinical usefulness of the glycemic parameters. A total of 11 women (6.5%) developed early postpartum diabetes. Apart from family history of diabetes (p = 0.052), anthropometric, maternal, and neonatal clinical parameters showed no association with early postpartum diabetes in univariate analyses. The level of fasting glucose, and both the glucose challenge test and diagnostic OGTT post-load glucose levels and glucose areas were associated with early postpartum diabetes. ROC curve analysis identifiedall three glucose challenge-test parameters, including fasting glucose concentration, as poor diagnostic tests, with a positive predictive value of approximately 22%, whereas the positive predictive value associated with the area under the diagnostic OGTT curve increased progressively over monitoring time from 20.6% to 100%. Using a 3-h OGTT glucose area threshold of 35.7 mmol.h/L resulted in 100% sensitivity and 100% specificity, identifying the 11 women who developed early postpartum diabetes. In summary, we can conclude from the present analysis that early postpartum diabetes is rare in GDM women (6.5%), and that the clinical usefulness of the total area under the diagnostic 3-h OGTT is superior to all other glycemic parameters for detecting early postpartum diabetes.

Adult↗

PubMed2006

Quantitative determination of erythrocyte folate vitamer distribution by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Given the role of folate in many disorders, intracellular distribution of folate vitamers is of potential clinical importance. In particular, accumulation of non-methyltetrahydrofolates due to altered partitioning of folate metabolism at the level of methylenetetrahydrofolate is of interest. METHODS: We describe a positive-electrospray liquid chromatography tandem mass spectrometry (LC-MS/MS) method that allows determination of erythrocyte folate vitamer distribution by accurately measuring both 5-methyltetrahydrofolate (5-methylTHF) and non-methyl folate vitamers. Whole blood lysates are deconjugated in ascorbic acid solutions, deproteinized, purified using folate-binding protein affinity columns, concentrated by solid-phase extraction (SPE) and evaporation, and separated on a C18 column within 6 min. RESULTS: The limit of quantification for both 5-methylTHF and non-methylTHF was 0.4 nmol/L (signal-to-noise >10). Intra- and inter-assay CVs for 5-methylTHF were 1.2% and 2.8%, respectively. Intra- and inter-assay CVs for non-methylTHF as a group were 1.6% and 1.5%, respectively. Recovery results were 97-107%. We measured 8-72% non-methyl folate vitamers in volunteers (n=5) with the methylenetetrahydrofolate reductase (MTHFR) 677 TT genotype. Concentrations ranged from 117 to 327 nmol/L and 23 to 363 nmol/L for 5-methylTHF and non-methylTHF vitamers, respectively. We measured 0-2% non-methylTHF vitamers in MTHFR 677 CC genotype volunteers. In addition, we found that storage of whole-blood samples in ascorbic acid at low pH resulted in 53-90% loss of the non-methylTHF fraction. CONCLUSION: This LC-MS/MS method accurately determines erythrocyte 5-methylTHF and non-methyl folate vitamers.

Chromatography, High Pressure Liquid↗

PubMed2005

Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inherited disorder of elastic tissue. We recently found that heterozygosity for the frequent (0.8% prevalence in Dutch population) R1141X mutation in the PXE gene coding for the ABCC6 transporter, is associated with a fourfold risk of premature coronary artery disease. Yet, it is not clear whether or not heterozygosity for this mutation results in a mild PXE phenotype. The objective of our study was to determine if skin and/or eye abnormalities related to a PXE phenotype could be found in patients with premature coronary artery disease, with and without the R1141X mutation. METHODS: R1141X mutation carriers with premature coronary artery disease (cases) and patients with premature coronary artery disease with no-or not known-mutation (controls) were studied. Cases and controls were examined for PXE-like skin changes and retinal angioid streaks, peau d'orange or pigment epithelium changes. RESULTS: 7 cases and 31 controls were analysed. In both the mutation-positive and the control group, skin inspection and eye fundus examination did not reveal any dermatological or ocular signs of PXE. CONCLUSIONS: Carriers for the ABCC6 R1141X mutation, which is frequent and confers a high risk of premature coronary artery disease, do not commonly have skin or eye abnormalities consistent with a mild PXE phenotype.

Adult↗

PubMed2005

Folic acid treatment increases homocysteine remethylation and methionine transmethylation in healthy subjects.

Folic acid treatment decreases plasma total homocysteine concentrations in healthy subjects, but the effects on homocysteine metabolism are unknown. In the present study, we investigated the effect of 3 weeks of oral treatment with 5 mg of folic acid on one-carbon flux rates in 12 healthy subjects, using in vivo stable isotope methods. In addition, we determined the effect of folic acid on blood concentrations of amino acids which may have regulatory roles in homocysteine metabolism, i.e. homocysteine, AdoMet (S-adenosylmethionine), AdoHcy (S-adenosylhomocysteine), serine and glycine. Primed, continuous infusions with [2H3-methyl-1-13C]methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation and homocysteine trans-sulphuration. Metabolic homocysteine clearance was defined as the ratio of trans-sulphuration and plasma homocysteine level. Folic acid treatment increased the homocysteine remethylation rate by 59% [95% CI (confidence interval), 13-97%; P = 0.02] and methionine transmethylation rate by 20% (95% CI, 3-41%; P=0.03). Plasma total homocysteine concentration (-18%; 95% CI, -28 to -9%; P<0.01) and the serine/glycine ratio (-20%; 95% CI, -63 to -6%; P<0.01) decreased significantly, and the AdoMet/AdoHcy ratio (11%; 95% CI, 1-20%; P = 0.02) increased significantly. Changes in one-carbon flux rates did not correlate significantly with changes in plasma concentration of these amino acids. In conclusion, folic acid treatment lowered plasma homocysteine concentration and increased whole-body remethylation and transmethylation flux in healthy subjects.

Adult↗

PubMed2005

Folate metabolism and cardiovascular disease.

Folate is a water-soluble vitamin that occurs in different chemical forms distinguished by their oxidation state and the specific type of one-carbon substitution. Folates occur in natural food sources as reduced methylated or formylated tetrahydrofolate. Folic acid is a synthetic analogue with no metabolic activity of its own. Pharmacological doses of folic acid cause it to appear in plasma, where it has unknown, but potentially adverse, effects. This review discusses folate absorption, body distribution, and intracellular folate metabolism. The main physiological functions of folate can be classified as methylation and DNA synthesis. Several mechanisms act in concert to regulate the folate metabolic pathways to ensure that both functions of folate are fulfilled properly. B-vitamin deficiencies and genetic polymorphisms (particularly the C677T mutation in the methylenetetrahydrofolatereductase gene) have multiple effects on folate metabolism. Impairment of the methylation cycle, for example, leads to hyperhomocysteinemia, a proposed atherothrombotic factor. However, methylation disturbances also result in hypomethylation of DNA and other molecules, which may also contribute to the pathogenesis of cardiovascular disease. As cardiovascular researchers, we should try to develop a more integrative view on folate metabolism, rather than focusing merely on hyperhomocysteinemia.

Biomarkers↗

PubMed2003

Turtle-associated human salmonellosis.

A patient who bred exotic turtles as a hobby presented with 2 episodes of severe diarrhea, the second of which was proven to be caused by turtle-associated salmonellosis that was contracted during treatment with a proton-pump inhibitor. The literature about reptile-associated salmonellosis is briefly reviewed.

Animals↗

PubMed2003

Steroids in adult men with type 1 diabetes: a tendency to hypogonadism.

OBJECTIVE: To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. RESULTS: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. CONCLUSIONS: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Adult↗

PubMed2002

Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD. METHODS AND RESULTS: To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; P<0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, P= 0.001). CONCLUSION: The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Adult↗

PubMed2002

Frequency of spontaneous fist clenching during routine blood pressure measurements and its effect on measurement accuracy.

BACKGROUND: Guidelines for office blood pressure reading techniques do not warn us about the possibility that patients may clench their fist during cuff-inflation. It is unknown how often patients do this, and what effect it has on measured blood pressure readings. DESIGN AND METHODS: We registered double blood pressure readings in 150 outpatient clinic subjects, who were not given specific instructions as to how to hold their hand during the procedure. If they clenched their fist during the first reading, they were asked to relax their hand during the second reading, and vice versa. Double readings with a relaxed hand on both occasions were registered in 100 matched control patients as well. RESULTS: Twenty-two of 150 patients (15%) spontaneously made a fist during the first reading. No systematic effect (lower or higher blood pressure) from making a fist was observed, but individual effects were often marked, as evidenced by the median absolute differences (regardless of '+' or '-' sign) between the duplicate readings: 5 (range 0-31) versus 3 (0-18) mmHg for systolic blood pressure, and 4 (0-22) versus 2 (0-16) mmHg for diastolic blood pressure in the study group versus the control group, respectively (P < or = 0.05). A different hypertension classification occurred twice as often when a fist was made during one of the two blood pressure readings than with two fistless readings (23 versus 12%, P = 0.04). CONCLUSION: About one out of every seven patients makes a fist during blood pressure taking. This can seriously affect measurement accuracy, and doubles the risk of misclassification of hypertension.

Blood Pressure↗

PubMed2002

Determinants of mild gestational hyperglycemia and gestational diabetes mellitus in a large dutch multiethnic cohort.

OBJECTIVE: The purpose of this study was to identify independent determinants of mild gestational hyperglycemia (MGH) and gestational diabetes mellitus (GDM) and to assess the correlation between fasting glucose and C-peptide levels among control, MGH, and GDM women. RESEARCH DESIGN AND METHODS: A total of 1,022 consecutive women were evaluated with a 1-h 50-g glucose challenge test (GCT) at between 16 and 33 weeks of gestation. Women with a capillary whole-blood glucose > or =7.8 mmol/l in the GCT underwent a 3-h 100-g oral glucose tolerance test (OGTT). On the basis of a positive GCT, the women with a positive OGTT were classified as GDM, whereas the women with a negative OGTT were classified as MGH. The following data were collected for all women: age, prepregnancy BMI, ethnicity, clinical and obstetric history, pregnancy outcome, and C-peptide level. RESULTS: A total of 813 women (79.6%) were normal, 138 (13.5%) had MGH, and 71 (6.9%) had GDM. There was a stepwise significant increase in mean fasting glucose (3.6 +/- 0.4, 3.9 +/- 0.4, and 4.7 +/- 0.7 mmol/l, respectively) and C-peptide level (0.60 [0.1-2.4], 0.86 [0.3-2.0], and 1.00 [0.5-1.6] nmol/l, respectively) among the three diagnostic groups. Maternal age, non-Caucasian ethnicity, and prepregnancy BMI were associated with GDM, whereas only maternal age and prepregnancy BMI were associated with MGH. A positive correlation between levels of fasting glucose and C-peptide was found in control women (r = 0.39 [95% CI 0.31-0.46]). A similar result was seen in MGH women (r = 0.38 [95% CI 0.23-0.52]), whereas the correlation between fasting glucose and C-peptide was nearly lost in GDM women (r = 0.14 [CI -0.09 to 0.36]). The fasting C-peptide-to-glucose ratio was reduced by 60% in GDM patients versus control subjects and MGH patients (0.41 +/- 0.25 vs. 0.70 +/- 0.20 and 0.73 +/- 0.23, P < 0.001). CONCLUSIONS: Of the well-known independent determinants of GDM, only maternal age and prepregnancy BMI were associated with MGH. It appears that additional factors promoting loss of beta-cell function distinguish MGH from GDM. One of these factors appears to be ethnicity.

Adult↗

PubMed2002

Hyperlactataemia in HIV-infected patients: the role of NRTI-treatment.

BACKGROUND: Long-term treatment with nucleoside reverse transcriptase inhibitors (NRTIs) can induce mitochondrial dysfunction, most severely represented by lactic acidosis. Diagnostic tests for mitochondrial dysfunction are lacking, although persistently elevated serum lactate might be a surrogate marker. OBJECTIVES: To determine the occurrence of hyperlactataemia in HIV-infected patients on NRTI-treatment and to evaluate the possible risk factors. METHODS: Cross-sectional analysis of lactic-acid levels in asymptomatic HIV-infected patients. Hyperlactactaemia was considered mild if between 2.0-5 mmol/l, serious if >5 mmol/l and lactic acidosis was defined as lactic acid levels >5 mmol/l with bicarbonate <20 mmol/l. Possible risk factors, such as current and preceding NRTI-treatment as well as treatment with non-nucleoside reverse transcriptase inhibitors or protease inhibitors and concurrent liver disease, were analysed. RESULTS: Two hundred and twenty three asymptomatic HIV-infected patients were studied, including 174 patients (78%) on NRTI treatment, 12 patients (5%) treated without NRTIs and 37 patients (17%) not treated. Mild hyperlactataemia was found in 42 patients (19%), from whom 38/42 (90%) were NRTI-treated and the remaining patients (4/42, 10%) received no treatment (chi2, P<0.05). The significant risk factors for hyperlactataemia in the univariate analysis were NRTI-treatment as a group (P=0.03) and elevated ALT (P=0.008). In multivariate analysis NRTI use (P=0.05) and ALT level (P=0.03) remained a significant determinant of hyperlactataemia. Among the different individual NRTIs, a stavudine-containing (P=0.004) and a zalcitabine-containing (P=0.07) regimen were most notably associated with the development of hyperlactataemia, whereas for the combinations of NRTIs, such association was only found for stavudine/lamivudine (P=0.05). CONCLUSIONS: A correlation between hyperlactataemia and NRTI treatment was found, but the value of routine lactate measurement for individual treatment monitoring remains uncertain.

Acidosis, Lactic↗