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Aeilko H Zwinderman

Publications and source records attributed to Aeilko H Zwinderman.

105 records · Page 6Linked to original sources
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

Asymptomatic worsening of airway inflammation during low-dose allergen exposure in asthma: protection by inhaled steroids.

Asthma is a chronic inflammatory disease that persists even during adequate therapy and asymptomatic episodes. We questioned whether "silent" chronic allergen exposure can induce and maintain airway inflammation and whether this still occurs during regular treatment with inhaled steroids. Twenty-six patients with house dust mite allergy and mild asthma (dual responders) participated in a parallel, double-blind study. All patients inhaled a low-dose of allergen on 10 subsequent working days (Days 1-5, 8-12). They were treated with 400 micro g budesonide once daily (n = 13) or placebo (n = 13) from Days -3 to 19. At baseline (Day -6) and on Days 5, 12, and 19 we measured the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)), and percent eosinophils, interleukin (IL)-5/interferon-gamma messenger RNA ratio (in sputum cells by real-time reverse transcription-polymerase chain reaction [RT-PCR]), and eosinophilic cationic protein (ECP) in induced sputum. Symptoms, peak expiratory flow (PEF), FEV(1), and exhaled nitric oxide (NO) were recorded repeatedly during the study. In the placebo group, repeated low-dose allergen exposure resulted in a significant increase in sputum eosinophils (p = 0.043), ECP (p = 0.011), IL-5/IFN-gamma messenger RNA ratio (p = 0.04), and in exhaled NO (p = 0.001), without worsening of symptoms, PEF, or baseline FEV(1) (p > 0.07). In the budesonide group, the changes in PC(20), sputum ECP, and exhaled NO were significantly different as compared with the placebo group (p < 0.03). We conclude that repeated low-dose allergen exposure in asthma can lead to airway inflammation without worsening of symptoms, which can be prevented by inhaled steroid treatment. This suggests that antiinflammatory therapy is beneficial during allergen exposure, even during asymptomatic episodes.

Administration, Inhalation↗
PubMed2002

Delayed graft function is characterized by reduced functional mass measured by (99m)Technetium-mercaptoacetyltriglycine renography.

BACKGROUND: The mechanism that underlies delayed graft function (DGF) is still poorly defined. Previous studies using tubular function tests have shown that postischemic injury to the renal transplants results in profound impairment of paraimmunohippurate (PAH) extraction through the tubules. METHODS: Using (99m)Technetium-mercaptoacetyltriglycine ((99m)Tc-MAG3) renography and tubular function slope (TFS), a study of the tubular uptake of (99m)Tc-MAG3 was undertaken in a prospective study of renal transplant recipients with immediate graft function (IGF) and those with DGF. RESULTS: A total of 37 consecutive recipients of a cadaveric graft and 5 kidneys from living donors was evaluated within 48 hours after transplantation and in week 2, months 3 and 6, and 3 years after transplantation. In addition to the protocol scans, recipients with DGF were examined every other day until function was resumed. Repeated measurement two-way analysis of variance and a change point analysis were performed to determine the difference in the follow-up of TFS values between the two groups. Fourteen patients were classified as having DGF and 28 immediate graft function. In the DGF group, the initial TFS value was significantly lower than in the immediate graft function group (0.54 [+/-0.01] and 1.75 [+/-0.16], respectively; P=0.002), a difference that persisted for up to 3 years. Change point analysis revealed that the postischemic tubular excretion improved with time in both groups in the first 3 to 4 weeks, but both groups remained different up to 3 years after transplantation. Multivariate analysis revealed that only the cold ischemic time was an independent risk factor for a low TFS value. After the initial recovery from postischemic injury, the TFS may be used as a marker for functional renal mass. CONCLUSION: We propose that the tubular defect in DGF, as defined by (99m)Tc-MAG3 renography, is irreversible and may be a marker of initial graft function.

Adult↗
PubMed2002

Estramustine phosphate combined with orchidectomy as first-line therapy in patients with prostate carcinoma. Effect of age on survival.

BACKGROUND: The role of age as a prognostic factor for survival remains debatable in patients with prostate carcinoma. METHODS: The authors conducted a retrospective study of the significance of age as a prognostic factor for survival and progression free survival in 386 patients who underwent orchidectomy for locally advanced or metastatic prostate carcinoma, 75% of whom had T0-T4, M1 disease. After undergoing orchidectomy, 192 patients received no further therapeutic intervention, whereas 194 patients received additional treatment with estramustine phosphate (EMP) as first-line therapy. RESULTS: The findings confirmed that age was a significant prognostic factor for survival and progression free survival in patients with prostate carcinoma as well as a predictor of response to chemotherapy. The data also showed that, although combining orchidectomy with EMP appeared to be beneficial in younger patients, using this relatively more aggressive therapeutic approach as first-line therapy in older patients (age > or = 80 years) may shorten their survival. CONCLUSIONS: The current findings call for caution with the additional use of EMP as first-line therapy in older patient with prostate carcinoma.

Age Factors↗
PubMed2002

Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.

BACKGROUND: Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. METHODS AND RESULTS: In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (P<0.0001), a 34% increase in HDL cholesterol (P<0.0001), and a 7% decrease in LDL cholesterol (P=0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL2, HDL3, and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. CONCLUSIONS: We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (P=0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

Adolescent↗
PubMed2002

Strontium-89 (Metastron) and the bisphosphonate olpadronate reduce the incidence of spinal cord compression in patients with hormone-refractory prostate cancer metastatic to the skeleton.

Spinal cord compression (SCC) is a devastating complication of metastatic cancer. We investigated the potential beneficial effect of two palliative therapies--strontium-89 (Metastron) and the nitrogen-containing bisphosphonate olpadronate--on the incidence of SCC in hormone-refractory prostate cancer (HRPC) metastatic to the skeleton. We retrospectively studied 415 patients with histologically proven prostate cancer who underwent bone scintigraphy at the time of diagnosis and were followed up at the Leiden University Medical Center between 1990 and 1999. Medical or surgical castration was undertaken in 172 patients with evidence for skeletal metastases. Within 2 years, 147 of these patients (85%) developed HRPC associated with severe progressive bone pain. Palliative treatment was given to 131 patients in the form of local radiotherapy ( n=10), 89Sr ( n=46) or intravenous olpadronate ( n=66), with ( n=57) or without ( n=9) maintenance oral olpadronate. Nine patients received both 89Sr and olpadronate at various intervals. Sixteen patients who did not receive any of these treatments were used as historical controls. There was no significant difference in baseline characteristics between treatment modalities. The incidence of SCC was 17% in the whole group, and highest in controls receiving no palliation (50%). None of the patients treated with local radiotherapy, only 4% of patients receiving 89Sr and 21% of patients given olpadronate developed this complication. Our findings suggest a significant reduction in SCC in patients with symptomatic HRPC metastatic to the skeleton who receive palliative therapies. Local radiotherapy completely prevents the incidence of SCC, 89Sr leads to an important decrease in this complication and olpadronate induces a significant, albeit smaller decrease in the incidence of SCC. The use of these agents opens new avenues in the difficult management of patients with advanced prostate cancer who are most at risk of developing SCC.

Aged↗
PubMed2002

Detection of vein graft disease using high-resolution magnetic resonance angiography.

BACKGROUND: The application of previous magnetic resonance (MR) angiography techniques has enabled noninvasive differentiation between patent and occluded coronary artery bypass grafts. However, the detection of graft stenosis remains difficult. The purpose of our study was to determine the accuracy of high-resolution navigator-gated 3-dimensional (3-D) MR angiography in detecting vein graft disease. Methods and Results- MR angiography was performed in addition to coronary angiography with quantitative coronary analysis in 56 vein grafts from 38 patients (mean age 66.6+/-9.3 years), who presented with recurrent chest pain after bypass surgery. Eighteen grafts showed a luminal stenosis >/=50%, 11 grafts a stenosis >/=70%, and 6 grafts were occluded. All MR angiograms were evaluated independently by 2 blinded observers, who scored the presence of graft occlusion and graft stenosis >/=50% and >/=70% with a confidence level of 1 to 10. MR image quality was judged as insufficient in 6 grafts and these were excluded. Receiver-operator characteristic analysis revealed an area under the curve of 0.89 and 0.89 for identifying graft occlusion, 0.81 and 0.87 for stenosis >/=50%, and 0.82 and 0.79 for stenosis >/=70% for the 2 observers, respectively. Interobserver agreement in assessing graft occlusion and stenosis >/=50% and >/=70% was 94% (kappa=0.74, r=0.81), 72% (kappa=0.40, r=0.66), and 82% (kappa=0.53, r=0.72), respectively. CONCLUSIONS: High-resolution navigator-gated 3-D MR angiography allows not only good differentiation between patent and occluded vein grafts but also the assessment of vein graft disease with a fair diagnostic accuracy. This approach offers perspective as a noninvasive diagnostic tool for patients who present with recurrent chest pain after vein graft surgery.

Adult↗
PubMed2002

Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.

BACKGROUND: Decreased concentrations of HDL cholesterol are associated with increased cardiovascular risk. These concentrations are directly related to cholesterol efflux from cells-the first step and a key process in reverse cholesterol transport. Cholesterol efflux is mediated by the ATP-binding cassette A1 transporter (ABCA1), the rate-limiting step in the production of HDL. We aimed to assess the relation between cholesterol efflux, HDL concentrations, and arterial-wall changes in individuals with impaired ABCA1 function. METHODS: We investigated 30 individuals from families with ABCA1 mutations, and 110 controls matched for age, sex, and ethnic origin. We measured concentrations of HDL cholesterol in plasma and intima-media thickness of the carotid arteries by B-mode ultrasonography in all participants. We also measured cholesterol efflux from skin fibroblasts in nine individuals with ABCA1 mutations and in ten controls. FINDINGS: Individuals with ABCA1 mutations had lower amounts of cholesterol efflux, lower HDL cholesterol concentrations, and greater intima-media thicknesses than controls. An intima-media thickness at the upper limit of normal (0.80 mm) was reached by age 55 years in the ABCA1 heterozygotes, and at age 80 years in unaffected controls (p<0.0001). Additionally, strong positive correlations were seen between HDL cholesterol concentrations and cholesterol efflux (r=0.90, p=0.001), and negative correlations between apolipoprotein-AI-mediated (r=-0.61, p=0.030) and HDL-particle-mediated (r=-0.60, p=0.018) efflux and intima-media thickness in the ABCA1 mutation carriers. INTERPRETATION: These results show a direct relation between ABCA1-mediated cellular cholesterol efflux and arterial-wall thickness, and therefore suggest that increasing efflux could inhibit atherosclerosis progression before the manifestation of symptomatic cardiovascular disease.

ATP Binding Cassette Transporter 1↗
PubMed2002

Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo.

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.

Administration, Oral↗
PubMed2002

A meta-analysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization: evidence for publication bias.

BACKGROUND: The insertion/deletion polymorphism of the gene encoding angiotensin-converting enzyme is a controversial risk factor for restenosis after percutaneous transluminal coronary revascularization in patients. Genetic association studies addressing this issue are frequently hampered by insufficient power. Therefore, we conducted a meta-analysis of this association, taking into account the possibility of publication bias. METHODS: We used the MEDLINE database and reviewed citations in relevant articles to identify 12 studies. Information on the design of the studies, the detailed genotype distribution, the angiographic follow-up rate, and the restenosis rate were categorized by use of a standardized protocol. RESULTS: Overall, DD (deletion-deletion) homozygotes had a higher restenosis risk than II (insertion-insertion) carriers (odds ratio 1.22, 95% CI 1.04-1.44, P <.05). However, the published studies were significantly heterogeneous, especially those addressing in-stent restenosis. Smaller studies tended to have positive results more frequently, which is characteristic of publication bias. Correcting for publication bias, we estimated the odds ratio to be 1.15 (95% CI 0.98-1.32, not significant). None of the published studies met all rules of genetic epidemiology. CONCLUSION: We conclude that a clinically significant association of the angiotensin-converting enzyme polymorphism with restenosis after percutaneous transluminal coronary revascularization in patients is unlikely. This meta-analysis provides evidence that the pooled estimate based on published literature, which favors an association, is distorted by publication bias. Hence, screening for this mutation in clinical practice is not justified. Future research should preferentially focus on gene-gene interaction and comply with the rules of genetic epidemiology.

Angioplasty, Balloon, Coronary↗
PubMed2002

MR flow mapping in coronary artery bypass grafts: a validation study with Doppler flow measurements.

PURPOSE: To validate fast magnetic resonance (MR) flow mapping with intravascular Doppler flow measurements in vitro and in patients with nonstenotic and stenotic coronary artery bypass grafts. MATERIALS AND METHODS: MR and Doppler flow measurements were performed in a small-diameter flow phantom with physiologic flow conditions and at baseline and during adenosine stress in 27 grafts in 23 patients, who were scheduled for cardiac catheterization. At invasive analysis, the grafts were divided into those with stenosis of less than 50% (nonstenotic) and those with stenosis greater than or equal to 50% (stenotic). In vitro velocity values and velocity values in nonstenotic and stenotic grafts were compared with linear regression analysis, and the in vitro interstudy variability was determined. RESULTS: Excellent correlations in average peak velocity (r = 0.99, P <.001) and diastolic peak velocity (r = 0.99, P <.001) were demonstrated in vitro between MR and Doppler flow measurements, with less than 5% interstudy variability. MR and Doppler flow measurements revealed good correlations in peak velocity and velocity reserve both in nonstenotic (n = 20) (average peak velocity: r = 0.81, P <.001; diastolic peak velocity: r = 0.83, P <.001; velocity reserve: r = 0.56, P =.010) and stenotic (n = 7) (average peak velocity: r = 0.83, P <.001; diastolic peak velocity: r = 0.78, P =.001; velocity reserve: r = 0.70, P =.078) grafts. CONCLUSION: Fast MR flow mapping provides noninvasive measures of peak velocity and velocity reserve, which closely correlate with Doppler values both in vitro and in nonstenotic and stenotic grafts.

Adenosine↗
PubMed2002

Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension.

The efficacy and safety of oral pamidronate was examined in a double-blind, placebo-controlled trial in women and men with established osteoporosis. Seventy-eight postmenopausal women and 23 men with at least one prevalent vertebral fracture were randomized separately to 150 mg/day of pamidronate or placebo for 3 years followed by 150 mg/day of pamidronate for an additional 2 years. In addition, all patients received 400 U/day of cholecalciferol and 500 mg/day of elemental calcium. Pamidronate increased significantly bone mineral density of the lumbar spine (LS-BMD) and of the femoral neck (FN-BMD). The total increase in BMD of the spine after 5 years of treatment was 14.3%. Lateral spine radiographs were obtained at baseline and after 3 years of treatment. Fractures of previously normal vertebrae occurred in 15 of 45 patients treated with placebo (33.3%) and in 5 of 46 patients treated with pamidronate (11%). The relative risk was 0.33 (95% CI, 0.14-0.77). Treatment was well tolerated and there was no difference in gastrointestinal toxicity between pamidronate and placebo-treated patients. One hundred fifty milligrams daily of pamidronate is an effective and safe treatment of women and men with established osteoporosis.

Administration, Oral↗
PubMed2002

Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes.

OBJECTIVE: Mortality in type 1 diabetic patients with end-stage renal failure is high and dominated by coronary atherosclerotic events. With regard to prognosis, simultaneous transplantation of pancreas and kidney (SPK) may be superior to kidney transplantation alone (KTA) in type 1 diabetic patients, because normalization of blood glucose levels may reduce progression of coronary atherosclerosis and because it is well known that progression of coronary atherosclerosis is one of the major factors that determines clinical prognosis. However, no data are available on progression of coronary atherosclerosis after SPK. RESEARCH DESIGN AND METHODS: We performed an observational angiographic study comparing progression of coronary atherosclerosis, analyzed with quantitative coronary angiography, in patients with (n = 26) and those without (n = 6) a functioning pancreas graft after SPK, to test the hypothesis that normalization of blood glucose levels by SPK may indeed reduce progression of coronary atherosclerosis in type 1 diabetic patients and thereby improve prognosis. RESULTS: Mean follow-up was 3.9 years. Average glucose control was significantly worse for the patients without a pancreas graft than for patients with a functioning pancreas graft: 11.3 (SD 3.5) vs. 5.9 mmol/l (SD 1.1) (P = 0.03). Mean segment diameter loss (progression of diffuse coronary atherosclerosis) was 0.024 mm/year (SD 0.067) in patients with a functioning pancreas graft, compared with 0.044 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Minimum obstruction diameter loss (progression of focal coronary atherosclerosis) was 0.037 mm/year (SD 0.086) in patients with a functioning pancreas graft compared with 0.061 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Regression of atherosclerosis occurred in 38% of patients with a functioning pancreas graft compared with 0% of patients of whom the pancreas graft was lost (P = 0.035). CONCLUSIONS: Our study provides, for the first time, evidence that in patients who have undergone SPK, progression of coronary atherosclerosis in patients with a functioning pancreas graft is reduced compared with patients with pancreas graft failure. Our observation is an important part of the explanation for the observed improved mortality rates reported in type 1 diabetic patients with end-stage renal failure after SPK compared with KTA. In light of these findings described above, SPK must to be carefully considered for all diabetic transplant candidates.

Adult↗
PubMedDate not supplied

Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin.

OBJECTIVE: To investigate whether high-dose simvastatin therapy could reduce carotid and femoral artery intima-media thickness (IMT) in patients with familial hypercholesterolemia (FH) to prevent cardiovascular disease. BACKGROUND: Imaging of arterial walls with B-mode ultrasonography is increasingly used as a noninvasive surrogate marker of cardiovascular disease. Intervention trials using this modality have shown that by reducing risk factors, progression of atherosclerosis was inhibited. METHODS: After a washout period of 6 weeks, all patients with FH started monotherapy with simvastatin, 80 mg/d, for 2 years. The primary end point was the change (in millimeters) of the mean combined far-wall IMT of predefined carotid and femoral arterial segments at 2 years. RESULTS: We included a total of 153 patients with FH. Mean +/- SD combined baseline IMT was 1.07 +/- 0.23 mm. After treatment with simvastatin for 2 years, this IMT decreased by a mean of 0.081 mm (95% confidence interval, -0.109 to -0.053; P<.001), with its largest reduction in the femoral artery (-0.283 mm; P<.001). An actual decrease of combined IMT was seen in 69.8% of all patients. CONCLUSIONS: High-dose simvastatin therapy reduces arterial wall IMT in more than two thirds of the patients, with its largest effect on the femoral artery. Furthermore, patients with FH who were treated with both statin and antihypertensive medication experienced a significantly greater benefit in terms of IMT reduction.

Adult↗