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Biomedical subjects

D W Swinkels

Publications and source records attributed to D W Swinkels.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Diagnosis and treatment of primary hemochromatosis].

Chronic fatigue, arthralgia, infertility, impotence, cardiac disease, diabetes and abnormality of liver enzymes could point to the presence of haemochromatosis. A patient with one of these symptoms, a normal haemoglobin content, but an increased transferrin saturation and serum ferritin level most probably has a primary haemochromatosis. Most primary haemochromatoses have a genetic background. The diagnosis 'HFE-related haemochromatosis' is made when a homozygous Cys282Tyr mutation is found in the HFE-gene. However, in approximately 10% of the patients with the clinical features of primary haemochromatosis this mutation is absent. The treatment of primary haemochromatosis consists of regular phlebotomy. Liver biopsy is indicated if fibrosis, cirrhosis or another hepatic disease is suspected. Family screening of first-grade relatives is indicated for all patients with primary haemochromatosis.

Cysteine↗
PubMed1997

[Hereditary haemochromatosis: recent developments in diagnostics].

Hereditary haemochromatosis (HHC), a condition of abnormal iron absorption, is among the commonest diseases in humans. Early diagnosis is vital, because the disease is easily treated by phlebotomy to remove iron. Recently, mutations were identified in a HLA-class I-like gene, designated HFE and possibly associated with HHC. It was found that 83% of unselected HHC patients and more than 90% of patients with a clear family history of HHC, were homozygous for a single point mutation resulting in an amino acid substitution (Cysteine282Tyrosine) in the HFE protein. Although these data look compelling, they are not definitive proof that HFE is the haemochromatosis gene, but identification of these mutations will be of value in early diagnosis of haemochromatosis. However, the questions when to use the assay for detection of the Cys282Tyr mutation and how to interpret the results are not fully clear yet. Therefore, caution is still advocated when using molecular testing.

Heart Diseases↗
PubMed1997

The characterisation of leukaemias with the Sysmex NE-8000.

Blood samples from 118 patients with acute and chronic leukaemia and with more than 50% leukaemic cells were processed with the automated haematology analyser Sysmex NE-8000. For 92 out of these 118 the differences in the histograms and scattergrams of the NE-8000 could be used in an attempt to characterise the leukaemia. This interpretation of the histograms and scattergrams appeared to be highly suggestive of the distinction between lymphatic leukaemia and myeloid leukaemia, and could be indicative of the presence of either the chronic or acute form of both the lymphatic and myeloid leukaemias.

Acute Disease↗
PubMed1997

Detection of tumour DNA in serum of colorectal cancer patients.

Circulating tumour DNA has previously been detected in serum and plasma of patients with lung cancer and head and neck cancer. These observations could potentially lead to new, specific and non-invasive tools for diagnosis, prognosis and follow-up in neoplastic disease, if found to be a more general phenomenon. To test if tumour DNA is also present in serum of patients with colorectal cancer, we selected 14 colorectal cancer patients with advanced disease. In seven patients, K-ras mutations were detected in the primary tumour, using mutant-specific primers for point mutations in codon 12 or 13 of the K-ras gene. All patients were analysed for mutant DNA in serum. Tumour-specific point mutations, corresponding to the K-ras mutations found in the primary tumour were detected in the serum of all patients but one. No mutant K-ras could be detected in the serum of seven patients without K-ras mutations in the primary tumour. These results may be useful in assessing tumour burden in patients with neoplastic disease. Moreover, consecutive testing of serum tumour DNA after surgery or chemotherapy may be used as a tumour marker for recurrent disease.

Colorectal Neoplasms↗
PubMed1994

Pregnancy in a patient with homozygous familial hypercholesterolemia treated with long-term low-density lipoprotein apheresis.

The pregnancy and delivery of a subject with homozygous familial hypercholesterolemia (FH) and coronary artery disease (CAD) were monitored closely for signs of maternal and fetal distress. Biweekly treatment with low-density lipoprotein (LDL) apheresis using dextran-sulfate cellulose columns was continued throughout the pregnancy, and lipid and lipoprotein levels were evaluated. During the course of the pregnancy and delivery, no signs of maternal coronary insufficiency developed. Serial ultrasonographic measurements of fetal growth indices and the blood flow velocity waveforms (FVWs) of the uterine and umbilical artery did not reveal any sign of fetal growth retardation or insufficiency of the uteroplacental circulation, respectively. During pregnancy, time-averaged concentrations of serum total cholesterol (TC), LDL cholesterol (LDL-C), apolipoprotein (apo) B, and lipoprotein(a) [Lp(a)] showed a gradual decline. Notwithstanding LDL apheresis, a gradual twofold increase of serum triglyceride (TG) levels was found. In the second and third trimester, high-density lipoprotein cholesterol (HDL-C) levels showed a 55% increase that coincided with a 75% reduction in hepatic lipase activity in postheparin plasma, normalizing after parturition. After delivery, lp(a) levels showed an almost twofold increase, which could not be explained by the interruption of LDL apheresis alone, and may be caused by changes in gonadal steroids. Histologic examination of the placenta and the umbilical arteries revealed no atherosclerotic changes, infarctions, or lipid deposits. In general, long-term LDL apheresis in homozygous FH can delay the onset and complications of severe CAD. In case of a pregnancy, LDL apheresis seems feasible and should be continued during the pregnancy to prevent superimposed hyperlipidemia and placental insufficiency.

Adolescent↗
PubMed1993

Exploration of the single-stranded DNA-binding domains of the gene V proteins encoded by the filamentous bacteriophages IKe and M13 by means of spin-labeled oligonucleotide and lanthanide-chelate complexes.

Scrutiny of NOE data available for the protein encoded by gene V of the filamentous phage IKe (IKe GVP), resulted in the elucidation of a beta-sheet structure which is partly five stranded. The DNA-binding domain of IKe GVP was investigated using a spin-labeled deoxytrinucleotide. The paramagnetic-relaxation effects observed in the 1H-NMR spectrum of IKe GVP, upon binding of this DNA fragment, could be visualized using two-dimensional difference spectroscopy. In this way, the residues present in the DNA-binding domain of IKe GVP can be located in the structure of the protein. They exhibit a high degree of identity with residues in the gene V protein encoded by the distantly related phage M13 (M13 GVP), for which similar spectral perturbations are induced by such a spin-labeled oligonucleotide. Binding studies with negatively charged lanthanide-1,4,7,10-tetraazacyclodecanetrayl-1,4,7-10- tetrakis(methylene)tetrakisphosphonic acid (DOTP) complexes, showed that these complexes bind to IKe and M13 GVP at two spatially remote sites whose affinities have different pH dependencies. Above pH 7, there is one high-affinity binding site for Gd(DOTP)5-/M13 GVP monomer, which coincides with the single-stranded DNA-binding domain as mapped with the aid of spin-labeled oligonucleotide fragments. The results show that single-stranded DNA binds to conserved (phosphate binding) electropositive clusters at the surface of M13 and IKe GVP. These positive patches are interspersed with conserved or conservatively replaced hydrophobic residues. At pH 5, a second Gd(DOTP)(5-)-binding site becomes apparent. The corresponding pattern of spectral perturbations indicates the accommodation of patches of conserved, or conservatively replaced, hydrophobic residues in the cores of the M13 and IKe dimers.

Amino Acid Sequence↗
PubMed1993

Differences in the low density lipoprotein subfraction profile between oral contraceptive users and controls.

To investigate the effect of low dose oral contraceptives on the low density lipoprotein (LDL) subfraction profile, the distribution of the LDL subfraction patterns in 20 premenopausal women on oral contraceptive (OC) therapy and 41 premenopausal women not taking gonadal hormones was studied. The LDL subfraction patterns were identified by density gradient ultracentrifugation and each individual LDL subfraction pattern was characterized by the relative contribution of three major LDL subfractions: light, LDL1; intermediate, LDL2; and dense, LDL3 to total LDL. Serum lipid and lipoprotein levels were similar in OC users and controls, except for significantly higher triglyceride levels in OC users. As for the LDL subfraction patterns, among the OC users the mean relative contribution of dense LDL3 to total LDL was significantly higher than in the controls (32% +/- 8% vs. 26% +/- 13%, P < 0.05), whereas the relative contribution of light LDL1 to total LDL was significantly lower (27% +/- 8% vs. 34% +/- 10%, P < 0.01), indicating a higher prevalence of the more dense LDL subfraction patterns among OC users. Furthermore, the distribution of the LDL subfraction patterns in OC users (27% LDL1, 41% LDL2, and 32% LDL3) resembled that of men (25% LDL1, 43% LDL2, and 33% LDL3, n = 59). Statistical analysis revealed that OC use was significantly associated with a more dense LDL subfraction pattern, characterized by an increased relative contribution of LDL3 (+6%, P < 0.05) and a decreased relative contribution of LDL1 (-6%, P < 0.01), even after correcting for the influence of lipid and lipoprotein levels, which in controls were shown to have a significant relation to LDL3 and LDL1, respectively. So, independent of the lipid and lipoprotein levels, low dose OC alter the composition of LDL to a heavy, dense LDL subfraction profile, which reportedly has been associated with an increased risk of atherosclerosis.

Cholesterol↗
PubMed1993

Differences in LDL receptor-mediated metabolism of three low density lipoprotein subfractions by human monocyte-derived macrophages: impact on the risk for atherosclerosis.

The metabolism of three low density lipoprotein (LDL) subfractions by human monocyte-derived macrophages (HMDM) through the LDL receptor pathway was studied. The three LDL subfractions, very light LDL1, light LDL2 and heavy LDL3, were isolated from serum pools of normolipidemic subjects by density gradient ultracentrifugation. The LDL subfractions were shown to differ in molecular size and chemical composition but not in electrophoretic mobility on agarose gel. Cell specific association, cell specific degradation and stimulation of cholesteryl esterification were determined in parallel after incubation of HMDM with increasing amounts of LDL-protein of the three LDL subfractions. The experiments were repeated four times with freshly prepared LDL subfractions. Both the cell specific association and degradation increased more with increasing LDL-protein concentration for LDL1 than for LDL3 (p < 0.001). The results for LDL2 were intermediate between those for LDL1 and LDL3 and differed significantly from both (p < 0.05). For the stimulation of cholesteryl ester formation, the curves for LDL1 and LDL2 increased more with increasing LDL-protein concentration than that for LDL3 (p < 0.001); the results for LDL1 and LDL2 did not differ significantly from each other. These differences between LDL subfractions in cholesteryl esterification were independent of the cholesterol content of the LDL subfractions. The results show that LDL subfractions have different rates of LDL receptor-mediated catabolism by HMDM. As HMDM play an important role in the formation of atherosclerotic plaques, the differences between the LDL subfractions in catabolism by HMDM, may result in differences in atherogenicity between LDL subfractions isolated from normolipidemic subjects.

Analysis of Variance↗
PubMed1992

Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families.

A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions--LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml)--to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The penetrance of the more dense LDL subfraction patterns, characterized by values of K < 0, was dependent on age, gender, and, in women, on oral contraceptive use and postmenopausal status. Furthermore, multiple regression analysis revealed that approximately 60% of the variation in the LDL subfraction pattern could be accounted for by alterations in age, gender, relative body weight, smoking habits, hormonal status in women, and lipid and lipoprotein levels. In conclusion, our results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease.

Adult↗