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D W Swinkels

Publications and source records attributed to D W Swinkels.

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

Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) Study.

BACKGROUND: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. METHODS: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. RESULTS: The heritability (h(2) +/- SE) estimates were 0.23 +/- 0.07 (p < 0.0001) for iron, 0.29 +/- 0.09 (p < 0.0001) for ferritin and 0.28 +/- 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age(2) and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. CONCLUSION: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network.

Female↗
PubMed2006

Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap.

Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC-electrochemical detection. Compared to post-B12 supplementation values, homocysteine was higher (52.9 micromol/l vs. 16.8 micromol/l), RBC folate was lower (268.92 nmol/l vs. 501.2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94.5% vs. 67.4%), polyglutamate chain length was shorter (more tetra- and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency.

Chromatography, Liquid↗
PubMed2005

Impact of the introduction of a guideline on the targeted detection of hereditary haemochromatosis.

BACKGROUND: In 1998 a clinical guideline for the targeted, accurate and early detection and treatment of HFE-related hereditary haemochromatosis (HH), which comprises a test for the causative HFE-gene mutations, was introduced in our outpatient department. METHODS: The impact of this guideline was evaluated retrospectively. Data were acquired from medical records of patients with discharge diagnosis codes suggestive of HH (n=878 patients), obtained from a period before (n=422) and after guideline introduction (n=456). RESULTS: Combined measurements of serum transferrin saturation and serum ferritin rose from 12.2% (n=53) to 29.5% (n=138, p<0.001), leaving 70% of the patients eligible for HH not tested for iron parameters. The HFE-gene mutation detection test was correctly used in II (40.7%) of 27 tested patients and improperly interpreted in six (22.2%) of these 27 patients. Five new HH patients were diagnosed before and 13 after introduction. Seven of these 13 patients appeared to be incorrectly diagnosed, due to misinterpretation of laboratory results. Diagnostic costs of case detection for each accurately diagnosed patient were euro 2380 before and euro 2600 after introduction of the guideline. CONCLUSION: Evaluation of the introduction of a practical guideline for targeted HH detection reveals a low compliance with the guideline, resulting in both a small percentage of patients tested for HH and overdiagnosis of HH. Therefore, the introduction of the guideline should be combined with a more appropriate implementation strategy which includes education on its most critical points, i.e. the indication and interpretation of the iron parameters and the HFE genotype.

Biopsy↗
PubMed2003

[From gene to disease; HFE-mutations in primary haemochromatosis].

Primary haemochromatosis is an autosomal recessive disorder with a high prevalence (1 in 200-400) among North-Europeans. Approximately 64-100% of patients with primary haemochromatosis are homozygous for a missense mutation that alters a major-histocompatibility-complex class I-like protein designated HFE (from 'haemochromatosis'). This predominant mutation is a substitution of cysteine to tyrosine at amino acid residue 282 (Cys282Tyr) in the alpha 3-domain of the HFE protein. This mutation in the HFE protein in the intestinal crypt cells is supposed to lead to up-regulation of iron transporters for dietary iron in the mucosal cells at the tip of the duodenal villi. As a consequence, an excess of absorbed iron accumulates in the major organs of the HFE-mutated patients, leading to multi-organ dysfunction. A second mutation, His63Asp, in the HFE-gene is enriched in primary haemochromatosis patients who are concomitantly heterozygous for the Cys282Tyr-mutation. However, its role in the pathophysiology of primary haemochromatosis is not yet clear. A small subgroup of patients with primary haemochromatosis do not have mutations in HFE; for some of them the genetic basis has been determined. Homozygosity for the Cys282Tyr-mutation plus biochemical and clinical evidence of iron overload renders the diagnosis of HFE-related primary haemochromatosis indisputable. In other cases, liver biopsy remains the gold standard for the diagnosis of primary haemochromatosis. First-degree relatives of index patients should be screened for the disease.

Amino Acid Substitution↗
PubMed2003

[Diagnosis of 5 patients with possible primary hemochromatosis].

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.

Adult↗
PubMed2003

Increased total cell-free DNA in the serum of pregnant women carrying a fetus affected by trisomy 21.

OBJECTIVE: Analysis of the levels of cell-free fetal and total DNA in serum of women carrying a male fetus affected by trisomy 21, and comparison of these levels with those in women carrying a normal male fetus. METHODS: DNA was extracted from archived second-trimester maternal serum samples collected as part of a prenatal screening program. A total of 10 cases with trisomy 21 male fetuses were compared with 10 controls (male fetuses) with samples matched for duration of storage and gestational age. Real-time quantitative PCR of the SRY and albumin genes was used to quantify fetal and total DNA respectively. RESULTS: The median fetal DNA level in the group of 10 pregnancies with trisomy 21 was 31.98 cell-equivalents per mL compared to 34.06 in the control group. The difference was not significant. The median total DNA level in women with a trisomy 21 fetus was significantly higher (P = 0.029) than that in controls (36 152.6 vs 5832.81 cell-equivalents per mL). CONCLUSIONS: Although we could not confirm previous studies of an increased amount of fetal DNA in pregnancies affected by trisomy 21, we did find increased levels of total DNA. The possible reasons for these observations are discussed with respect to previous findings. Larger studies are needed to elucidate the true value, if any, of measurement of fetal and total DNA in maternal serum in the context of prenatal screening for chromosomal abnormalities.

Adolescent↗
PubMed2002

Primary haemochromatosis: a missed cause of chronic fatigue syndrome?

OBJECTIVE: To determine whether patients previously diagnosed as chronic fatigue syndrome (CFS) actually have primary haemochomatosis (PH). METHODS: The setting was a Dutch referral centre. Transferrin saturation (TS) was retrospectively evaluated in banked blood samples of 88 patients diagnosed as CFS. Patients with elevated TS values were asked to provide a new overnight fasting blood sample for a second determination of TS and measurement of serum ferritin. The DNA was investigated for mutations in the HFE gene when one of these iron parameters was elevated. RESULTS: For 19 out of 88 patients with CFS an elevated TS was found. A new blood sample was obtained from 11 of these 19: six had increased TS and two had elevated serum ferritin values. These eight patients were neither C282Y homozygotes nor compound C282Y-H63D heterozygotes. In the eight cases where no new blood samples could be obtained, the TS was > 50% for two of the five men and < 45% for the three female patients. CONCLUSION: In a group of 88 CFS patients we could exclude PH in all but two of them (prevalence 2.3%; 95% confidence interval 0-5.5%). In our population of CFS patients PH is not more common than in a control population of northern European descent (prevalence 0.25-0.50%).

Adult↗
PubMed2001

Nutrient-dense foods and exercise in frail elderly: effects on B vitamins, homocysteine, methylmalonic acid, and neuropsychological functioning.

BACKGROUND: Frail elders are at risk of suboptimal micronutrient status, functional decline, and neurologic disorders. The influence of oral multimicronutrients in physiologic doses and of moderately intense physical exercise on homocysteine (Hcy), methylmalonic acid (MMA), and neurologic functioning have not yet been investigated. OBJECTIVE: Our goal was to determine the effects of enriched foods and exercise on blood vitamins, Hcy, MMA, and neuropsychological functioning in the frail. DESIGN: A 17-wk randomized controlled intervention trial was used to study 1) enriched foods plus a social program, 2) regular foods plus exercise, 3) enriched foods plus exercise, and 4) regular foods plus a social program. Enriched foods contained multiple micronutrients (25-100% of the Dutch recommended dietary allowances); exercises focused on strength, coordination, flexibility, and endurance. Vitamin (cobalamin, red blood cell folate, and pyridoxal 5'-phosphate), Hcy, and MMA concentrations were measured and 2 neuropsychological tests were conducted. RESULTS: Vitamin concentrations were higher in the supplemented groups than in the unsupplemented groups (P < 0.001; total n = 130). Compared with baseline, cobalamin in the supplemented groups was increased by 22%, plasma folate by 101%, red blood cell folate by 87%, and pyridoxal 5'-phosphate by 68%. Concentrations in the unsupplemented groups changed by -2%, -6%, 1%, and -13%, respectively. Hcy decreased by 25% and MMA by 30% in the supplemented groups, compared with a small increase in Hcy (2%) and decrease in MMA (9%) in the unsupplemented groups. Exercise did not significantly affect vitamin, Hcy, or MMA concentrations. No significant effect of either intervention was observed on the neuropsychological tests. CONCLUSIONS: The decrease in Hcy and MMA in frail elders confirms a subclinical metabolic deficiency state. Enriched foods containing physiologic amounts of micronutrients have a beneficial effect on these metabolites. No effects of B vitamins on mental health were identified.

Aged↗
PubMed2000

Quantitative measurement of telomerase reverse transcriptase (hTERT) mRNA in urothelial cell carcinomas.

Telomerase reverse transcriptase (hTERT) messenger RNA has been detected in 95% of bladder tumors using RT-PCR. In this study, we quantified the expression of hTERT in 35 bladder urothelial cell carcinomas and in 6 normal bladder epithelia using a real-time quantitative PCR assay. hTERT expression was detected in all 35 urothelial cell carcinomas of varying grade and stage, but not in normal tissue samples. An increase in both pathological grade and clinical stage as prognostic parameters correlated with increased hTERT expression. Using different cutoff values for grades and stages, normalized hTERT expression values could discriminate among low, medium, and high grade tumors and between superficial and muscle-invasive tumors. We conclude that standardized real-time measurement of hTERT expression can be used for early tumor detection and may be used for determination of prognosis in urothelial cell carcinomas of the bladder.

Carcinoma, Transitional Cell↗
PubMed2000

Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial.

BACKGROUND: An elevated plasma homocysteine concentration is a putative risk factor for cardiovascular disease. Observational studies have reported an association between coffee consumption and plasma homocysteine concentrations. OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in a crossover trial. We used unfiltered coffee so as to include the possible effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered cafetière (French press) coffee daily for 2 wk. Such coffee is rich in the cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34) received water, milk, broth, tea, and chocolate drinks instead of coffee. After a washout period of 8 wk, both groups received the alternate intervention for another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8 to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine concentrations in volunteers with normal initial concentrations. It is unclear whether the effect is caused by the cholesterol-raising diterpenes present exclusively in unfiltered coffee or by factors that are also present in filtered coffee.

Adult↗
PubMed2000

New method for faecal fat determination by mid-infrared spectroscopy, using a transmission cell: an improvement in standardization.

Current techniques used in clinical laboratories for faecal fat determination, such as the Van de Kamer method, are not very accurate or precise. This became apparent when results obtained by different laboratories were compared, and could explain the disappointing performance of near-infrared and mid-infrared spectroscopy since the accuracy of these techniques depends upon the accuracy of the calibration used (i.e. inaccurate wet chemical analysis). In order to improve standardization, we developed and tested a new quantitative method in three laboratories, based on Fourier transform infrared (FT-IR) spectroscopy. Fatty acids were extracted from faecal samples with acidified petroleum ether-ethanol and the extracts were dried and dissolved in chloroform. An infrared spectrum of the extracts was recorded in the range 4000-650 cm(-1), using an infrared transmission cell. Standard mixtures of stearic and palmitic acids (65:35) were used for calibration. Quantification was based on the absorbance band of the CH2 group (2855 cm(-1)) of free fatty acids and fatty acid glycerol esters. The calibration curve showed excellent linearity. The correlation coefficient between the titrimetric Van de Kamer and FT-IR methods was 0.96 (y = 1.12x-0.02, standard error of prediction = 0.89 g% fat). No significant difference was found when the FT-IR results of 28 faecal samples from patients were compared between two different university hospital laboratories. The new FT-IR method, using primary standards, is simple and rapid, and provides satisfactory intra- and inter-laboratory precision for the diagnosis and monitoring of steatorrhoea.

Calibration↗
PubMed2000

Glomerular filtration rate by single-injection inulin clearance: definition of a workable protocol for children.

The total serum clearance of inulin after a single intravenous injection is an established method for the determination of the glomerular filtration rate (GFR). To optimize this procedure in children, we analyzed 117 serum inulin time-decay curves in 59 children (age range 1.3-15.2 years)with renal disease. It was found that the two-compartment model fitted statistically better to the disappearance curves of serum inulin than the one-compartment model. The sampling frequency could be reduced from 12 to a minimum of seven data points (t=0, 10, 20, 30, 65, 120 and 240 min) in 4 h without a relevant change in the fit of the two-compartment model to the date or in the calculated clearance of serum inulin. We conclude that, by using a standardized 'seven-sample schedule', followed by a two-compartment analysis, the single-injection serum clearance of inulin is a suitable compromise between practical convenience and clinical accuracy for the determination of the GFR in children.

Adolescent↗
PubMed2000

Real-time quantification of human telomerase reverse transcriptase mRNA in tumors and healthy tissues.

BACKGROUND: Expression of the hTERT gene, which codes for the catalytic subunit of telomerase, is associated with malignancy. We recently developed a real-time reverse transcription-PCR assay, based on TaqMan technology, for accurate and reproducible determination of hTERT mRNA expression (Lab Investig 1999;79:911-2). This method may be of interest for molecular tumor diagnostics in tissues and corresponding body fluids, washings, or brushes. METHODS: In this study, we measured hTERT expression in a subset of healthy tissues and tumors to select those tumor types with the best potential for quantification of hTERT in corresponding body fluids. To demonstrate the use of the method in body fluids, we quantified hTERT expression in voided urine of patients with bladder cancer and controls. RESULTS: Real-time measurement of hTERT expression could discriminate between all healthy and malignant tissue samples from pancreas, lung, esophagus, and bladder, but not for colon tissues. Moreover, in five of nine (55%) urine samples, hTERT could be quantified. CONCLUSIONS: The present study demonstrates that accurate quantitative measurement of hTERT expression has high potential for discrimination between healthy and tumor cells in tissues and urine and supports future measurements in pancreatic fluid, bronchoalveolar lavage fluid, esophageal brushings, and urine or bladder washings.

DNA-Binding Proteins↗