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Biomedical subjects

Robin P F Dullaart

Publications and source records attributed to Robin P F Dullaart.

At least 19 recordsLinked to original sources
PubMed2026

Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.

BACKGROUND AND AIMS: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. METHODS: This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. RESULTS: Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. CONCLUSIONS: This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.

Humans↗
PubMed2006

Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy.

PURPOSE: To demonstrate the benefit of immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma (NFA) in perspective to the need for hormonal substitution and life expectancy. METHODS AND MATERIALS: Retrospective cohort analysis of 122 patients, operated for NFA between 1979 and 1998. Recurrence was defined as regrowth on computed tomography or magnetic resonance imaging. The occurrence of hormonal deficiencies was defined as the starting date of hormonal substitution therapy. RESULTS: Seventy-six patients had residual NFA after surgery and received immediate postoperative radiotherapy (Group 1); three patients developed a recurrence, resulting in a 95% local control rate at 10 years. Twenty-eight patients had residual NFA after surgery, but were followed by a wait-and-see policy (Group 2). Sixteen developed a recurrence, resulting in a local control rate of 49% at 5 years and 22% at 10 years (p < 0.001 compared with Group 1). There were no differences between Group 1 and 2 regarding the need for substitution with thyroid hormone, glucocorticoids, and sex hormones before first surgery, directly after surgery and at end of follow-up. There were no differences in hormone substitution free survival between Group 1 and Group 2 during the study period after first surgery. Life expectancy was similar in Group 1 and 2, and their median life expectancy did not differ from median life expectancy in the general population. CONCLUSIONS: Immediate postoperative radiotherapy provides a marked improvement of local control among patients with residual NFA compared with surgery alone, without an additional deleterious effect on pituitary function and life expectancy.

Adenoma↗
PubMed2006

An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study.

BACKGROUND: Several cholesteryl ester transfer protein (CETP) polymorphisms affect high-density lipoprotein (HDL) cholesterol, but the impact of CETP gene variants on incident coronary disease in the general population is uncertain after correction for their effect on HDL cholesterol. DESIGN: We determined relationships between the CETP -629C-->A promoter (n = 8141), the TaqIB (n = 8289), and the I405V (n = 8265) polymorphisms, serum lipids, C-reactive protein, and clinical factors with incident coronary heart disease (defined as death from or hospitalization for myocardial infarction, ischemic heart disease, or coronary intervention) during a median of 4.94 yr follow-up. SUBJECTS: A predominantly Caucasian general population was studied. RESULTS: HDL cholesterol was 0.08 mmol/liter higher in -629A carriers than in -629CC homozygotes (P < 0.001). The unadjusted coronary hazard was 1.26 [95% confidence interval (CI), 0.95-1.68; P = 0.11] in A carriers compared with CC homozygotes and increased to 1.46 (95% CI, 1.10-1.95; P = 0.01) after adjustment for HDL cholesterol. This effect remained after additional adjustment for apolipoprotein A-I, triglycerides, C-reactive protein, age, and gender. Likewise, the HDL-cholesterol-adjusted hazard ratio was also higher in AA than in CC homozygotes (hazard ratio, 1.72; 95% CI, 1.22-2.42; P < 0.01). Similar findings were obtained with the TaqIB polymorphism. The 405V allele was weakly associated with incident coronary heart disease after HDL cholesterol adjustment (P = 0.09). CONCLUSIONS: A common CETP promoter polymorphism, which beneficially contributes to higher HDL cholesterol, is paradoxically associated with increased incidence of coronary disease in the general population. Thus, CETP gene variation may affect coronary risk apart from the level of HDL cholesterol.

Apolipoprotein A-I↗
PubMed2005

Cellular cholesterol efflux to plasma from proteinuric patients is elevated and remains unaffected by antiproteinuric treatment.

BACKGROUND: Lipid derangements are assumed to contribute to the elevated cardiovascular risk in proteinuric patients. The impact of proteinuria on reverse cholesterol transport (RCT) is unknown. The first step in RCT, cellular cholesterol efflux to plasma, may be altered in proteinuria, consequent to changes in pre-beta high-density lipoprotein (HDL) formation and plasma phospholipid transfer protein (PLTP) activity. METHODS: In six non-diabetic male patients with nephrotic-range proteinuria and 12 matched healthy men, plasma (apo)lipoproteins, pre-beta HDL formation, PLTP activity as well as the ability of plasma to promote cholesterol efflux out of cultured human skin fibroblasts were determined. These variables were also measured in response to antiproteinuric treatment, consisting of single and dual RAAS blockade by losartan and lisinopril. RESULTS: Plasma total cholesterol (P<0.05), triglycerides (P<0.05), apolipoprotein (apo) A-I (P<0.001), apo B (P<0.001), PLTP activity (P<0.005) and pre-beta HDL formation (P<0.001) were higher in proteinuric patients. Cellular cholesterol efflux to plasma from proteinuric patients was 41% higher than to plasma from healthy subjects (P<0.001). Reduction of proteinuria from 5.0 to 1.4 g/day by dual RAAS blockade was associated with a 23% reduction in plasma apo B levels (P<0.05). Pre-beta HDL formation and plasma PLTP activity did not change significantly. Combined antiproteinuric treatment did not reduce the elevated cellular cholesterol efflux. CONCLUSION: Cellular cholesterol efflux to plasma from patients with nephrotic-range proteinuria is enhanced, in conjunction with elevated pre-beta HDL formation and plasma PLTP activity. These changes may attenuate the cardiovascular risk associated with proteinuria-associated hyperlipidaemia. Antiproteinuric therapy lowers plasma apo B, but does not affect cell-derived cholesterol efflux, suggesting that this therapy beneficially affects cardiovascular risk in proteinuric patients.

Adult↗
PubMed2005

Repeated [131I]metaiodobenzylguanidine therapy in two patients with malignant pheochromocytoma.

CONTEXT: Approximately 10% of pheochromocytomas are malignant with a 5-yr survival rate of less than 40%. Promising results have been published on single high-dosage [131I]metaiodobenzylguanidine ([131I]MIBG) treatment for malignant pheochromocytoma. We present our experience with multiple intermediate-dosage [131I]MIBG therapy instead of single high-dosage therapy. SETTING AND PATIENTS: The study took place at University Medical Centers and included two patients (one male, 36 yr of age, and one female, 43 yr of age) with widely spread metastatic pheochromocytoma and bad prognosis because of liver and lung metastases. INTERVENTIONS: Instead of a single high dosage, these two patients were treated with multiple intermediate dosages of [131I]MIBG. The first patient received 37 GBq (1 Ci) [131I]MIBG in five sessions [7400 MBq (200 mCi) each; interval range, 2-11 months]; the second patient received 66.6 GBq (1.8 Ci) [131I]MIBG in 12 sessions [5550 MBq (150 mCi) each; interval range, 2-14 months]. OUTCOME MEASURES: We measured efficacy, toxicity, and survival. RESULTS: Both patients had a complete symptomatic response and a partial tumor volume response. The first patient had a partial biochemical response, the second a complete biochemical response. In both cases, toxicity has been confined to nausea during treatment. Hematological toxicity was minimal, and both patients stayed euthyroid. The survival (so far) of these patients was 5 yr (clinical case 1) and 16 yr (clinical case 2) after initial diagnosis. CONCLUSIONS: Repeated intermediate-dosage [131I]MIBG treatment appears to be a reliable and well-tolerated radionuclide therapy and might be a useful adjunct in patients with malignant pheochromocytoma, providing longstanding palliation and prolonged survival.

3-Iodobenzylguanidine↗
PubMed2005

The effect of cholesteryl ester transfer protein -629C->A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides.

CONTEXT: The -629C-->A cholesteryl ester transfer protein (CETP) promoter polymorphism is a determinant of HDL cholesterol (HDL-C). The effect of the closely linked CETP TaqIB polymorphism on HDL-C has been suggested to be modified by obesity and hyperinsulinemia. OBJECTIVE: Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, we hypothesized that triglycerides modify the effect of the CETP -629C-->A promoter polymorphism on HDL-C. DESIGN: In 7083 nondiabetic subjects of the PREVEND population, the -629C-->A promoter polymorphism, HDL-C, serum triglycerides, waist circumference, and insulin resistance (HOMA(ir)) were determined. Serum apolipoprotein A-I was available in 6948 subjects. The TaqIB polymorphism was also assessed. SETTING: The study is set in the general community. RESULTS: HDL-C and serum apolipoprotein A-I were on average 0.14 mmol/liter and 0.05 g/liter higher in -629AA (22.9%) compared to -629CC (26.8%) homozygotes (P < 0.001 for both). This genotype effect on HDL-C was on average 0.15 mmol/liter in the lowest triglyceride tertile but only 0.08 mmol/liter in the highest tertile (P < 0.01). Multiple regression analysis showed that HDL-C was determined by the CETP promoter variant (P < 0.001), gender (P < 0.001), triglycerides (P < 0.001), and interactions between triglycerides and genotype (P < 0.05), between triglycerides and gender (P < 0.05), and between genotype and gender (P < 0.05), independently from waist, HOMA(ir), alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The -629C-->A promoter polymorphism did not interact with obesity and HOMA(ir) on HDL-C. CONCLUSIONS: The HDL-C-raising effect of the CETP -629A allele is diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides.

Adult↗
PubMed2005

Analysis of cortisol and other stress-related hormones in patients with Ménière's disease.

OBJECTIVE: To evaluate cortisol and catecholamine levels in patients with Ménière's disease. STUDY DESIGN: Prospective, controlled study. SETTING: Tertiary referral center. PATIENTS: Thirty patients with Ménière's disease and 18 healthy controls. MAIN OUTCOME MEASURES: Serum and saliva cortisol, serum cortisol after the dexamethasone suppression test, urine free cortisol, and urine catecholamines. RESULTS: The serum and saliva cortisol levels were higher in Ménière's patients compared with their control group: 440 +/- 127 (n = 28) versus 366 +/- 90 (nmol/L) (n = 18) and 17.2 +/- 6.1 (n = 18) versus 11.6 +/- 4.6 (nmol/L) (n = 9), respectively. Both differences were significant (p < 0.05). There were no dissimilarities in urine cortisol or urine catecholamines for either group. Twenty-eight Ménière's patients were divided into two subgroups, namely, high- and low-cortisol groups, using a serum cortisol level cutoff point of 465 nmol/L (median). The total Ménière's disease time and the duration of tinnitus tended to be longer in the high-cortisol group (p = 0.07, two-tailed). The total Ménière's disease time was 13.5 +/- 9.9 years in the high-cortisol group and 7.1 +/- 7.4 years in the low-cortisol group (n = 14 for both). The subgroups were matched for age, gender, and unilaterally or bilaterally affected ears. CONCLUSION: Patients with Ménière's disease have higher serum cortisol levels. It is suggested that these higher cortisol levels are rather the result than the cause of this chronic disease, because patients affected longer seem to have higher cortisol levels. The exact impact of these higher cortisol levels on the inner ear and endolymph homeostasis is yet unknown.

Adult↗
PubMed2005

Plasma cholesteryl ester transfer is a determinant of intima-media thickness in type 2 diabetic and nondiabetic subjects: role of CETP and triglycerides.

We tested whether carotid artery intima-media thickness (IMT) is associated with plasma cholesteryl ester transfer (CET) and/or the plasma cholesteryl ester transfer protein (CETP) concentration in type 2 diabetic and control subjects. In 87 male and female subjects with type 2 diabetes (nonsmokers, no insulin or lipid-lowering drug treatment) and 82 control subjects, IMT, plasma CET, CETP mass, and lipids were determined. HDL cholesterol was lower, whereas IMT, pulse pressure, plasma triglycerides, and plasma CET and CETP concentration were higher in diabetic patients versus control subjects. In diabetic patients, plasma CET was positively determined by triglycerides (P < 0.001), non-HDL cholesterol (P < 0.001), CETP (P = 0.002), and the interaction between CETP and triglycerides (P = 0.004). In control subjects, plasma CET was positively related to triglycerides (P < 0.001) and non-HDL cholesterol (P < 0.001). HDL cholesterol was inversely related to plasma CET in each group (P < 0.01 for both). IMT was positively associated with plasma CET in diabetic (P = 0.05) and control (P < 0.05) subjects after adjustment for age, sex, and pulse pressure. No independent relationship with plasma CETP mass was found. Plasma CET is a positive determinant of IMT. Plasma CETP mass, in turn, is a determinant of CET with an increasing effect at higher triglycerides. These data, therefore, provide a rationale to evaluate the effects of CETP inhibitor treatment on plasma CET and on cardiovascular risk in diabetes-associated hypertriglyceridemia.

Adult↗
PubMed2005

Post-heparin plasma lipoprotein lipase, but not hepatic lipase activity, is related to plasma adiponectin in type 2 diabetic patients and healthy subjects.

The aim of this study was to determine the relationships of plasma adiponectin with post-heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities, and to evaluate whether plasma adiponectin contributes to diabetes-associated dyslipidaemia. Plasma adiponectin, post-heparin plasma lipase activities, lipoproteins and insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were measured in 24 male type 2 diabetic patients and 24 age-matched healthy men. Plasma triglycerides (P < 0.01) and apolipoprotein B levels (P < 0.01) were higher, and HDL cholesterol was lower (P < 0.05) in type 2 diabetic patients. Plasma adiponectin, as well as LPL and HL activities were not significantly different between diabetic and healthy subjects. Multiple regression analysis showed that LPL activity was positively related with plasma adiponectin (P < 0.05). In contrast, HL activity was positively related with body mass index (P < 0.02) and waist/hip ratio (P < 0.05, multiple r = 0.74), but not with plasma adiponectin. Plasma adiponectin was positively associated with insulin sensitivity (P = 0.001), age (P < 0.02) and LPL activity (P < 0.05, multiple r = 0.64), but not with the presence of diabetes and HL activity. Plasma triglycerides were negatively related with LPL activity (P = 0.002) and positively with the diabetic state (P = 0.001, multiple r = 0.58). HDL cholesterol was positively related with plasma adiponectin (P = 0.003) and negatively with HL activity (P < 0.02) as well as with the presence of diabetes (P = 0.05, multiple r = 0.59). We conclude that post-heparin plasma LPL activity, but not HL activity, is related with plasma adiponectin. Plasma adiponectin appears to be a determinant of plasma triglycerides via an effect on LPL activity. It seems unlikely that plasma adiponectin predicts the effects of the diabetic state as such on high plasma triglycerides and low HDL cholesterol.

Case-Control Studies↗
PubMed2004

A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease.

OBJECTIVES: We investigated the consequences of an apolipoprotein A-I (apoA-I) gene defect with regard to lipid metabolism, endothelial function, arterial wall thickness, and coronary artery disease (CAD) risk. BACKGROUND: Due to limited numbers of carriers of the apoA-I defects, data on the consequences of such defects have remained inconclusive. METHODS: Lipids and lipoproteins were measured in 54 apoA-I (L178P) carriers and 147 nonaffected siblings. Flow-mediated dilation (FMD) was assessed in 29 carriers and 45 noncarriers, and carotid intima-media thickness (IMT) could be determined in 33 heterozygotes and 40 controls. Moreover, CAD risk was evaluated for all apoA-I mutation carriers. RESULTS: Heterozygotes exhibited lower plasma levels of apoA-I (-50%; p < 0.0001) and high-density lipoprotein cholesterol (-63%; p < 0.0001). In addition, carriers had impaired FMD (p = 0.012) and increased carotid IMT (p < 0.001), whereas multivariate analysis revealed that heterozygotes had a striking 24-fold increase in CAD risk (p = 0.003). CONCLUSIONS: Heterozygosity for a novel apoA-I mutation underlies a detrimental lipoprotein profile that is associated with endothelial dysfunction, accelerated carotid arterial wall thickening, and severely enhanced CAD risk. Importantly, the extent of atherosclerosis in these subjects was similar to the burden of premature arterial wall abnormalities seen in patients with familial hypercholesterolemia. These data illustrate the pivotal role in humans of apoA-I in the protection against CAD.

Adult↗
PubMed2004

Diagnostic I-131 scintigraphy in patients with differentiated thyroid cancer: no additional value of higher scan dose.

OBJECTIVE: After initial treatment with total thyroidectomy and radioiodine ablation, most follow-up protocols for patients with differentiated thyroid carcinoma contain cyclic diagnostic I-131 imaging and serum thyroglobulin measurements. The applied diagnostic I-131 doses vary between 37 and 370 MBq. The aim of this study was to determine the yield of a diagnostic scan with 370 MBq I-131 in patients with a negative diagnostic scan with 74 MBq I-131. METHODS: Retrospective evaluation of 158 patients who received a high-dose diagnostic scan with 370 MBq I-131 because of a negative low-dose diagnostic scan with 74 MBq I-131. Special attention was paid to the patients with positive high-dose diagnostic scanning and undetectable serum thyroglobulin levels after thyroid hormone withdrawal. RESULTS: In 127 (80%) of patients the 370 MBq I-131 scan was negative, just like the preceding low-dose scan. In 31 (20%) of patients abnormal uptake was present on the 370 MBq diagnostic scan. In 19 of these 31 patients serum thyroglobulin was undetectable. In 15/19 the high-dose diagnostic scan proved either false positive or demonstrated clinically irrelevant minor ablation rests. In only four patients (2.5%) did the high-dose diagnostic scans reveal possibly relevant uptake caused by residual differentiated thyroid cancer. CONCLUSION: In 98% of patients a 370 MBq dose of I-131 for diagnostic WBS had no additional value. The combination of a low-dose diagnostic I-131 scan using only 74 MBq combined with a serum Tg level measurement proved sufficient for correct clinical decision making regarding whether the patient requires additional I-131 therapy.

Adolescent↗
PubMed2004

Familial occurrence of subacute thyroiditis associated with human leukocyte antigen-B35.

Subacute thyroiditis (SAT) is a spontaneously remitting inflammatory disorder of the thyroid, associated with human leukocyte antigen (HLA)-B35, and may be virally induced in genetically predisposed individuals. A 57-year-old Caucasian man presented with symptoms of hyperthyroidism as well as enlargement and tenderness of the thyroid. The patient had an elevated erythrocyte sedimentation rate, low thyrotropin (TSH) and elevated thyroxine and triiodothyroinine levels with suppressed 131I thyroidal uptake. He was diagnosed to have SAT. In the patient's family three sisters and one brother also had had SAT, as probably did the deceased father. Because of the familial occurrence HLA-typing was performed. All affected family members were heterozygous for HLA-B35. The family members lived more than 50 miles apart in different regions of The Netherlands and had SAT at different time points between 1986 and 2002, which in combination with HLA-B35 seems to highlight the importance of genetic influences as a risk factor for the development of SAT in this family. In conclusion, the case described here represents the second familial incidence and largest family reported so far with occurrence of SAT in association with HLA-B35.

Aged↗
PubMed2004

Lack of radiation optic neuropathy in 72 patients treated for pituitary adenoma.

The incidence of radiation optic neuropathy (RON) after external photon beam radiation therapy for nonfunctioning pituitary adenoma (NFA) is not well-studied. Retrospective review of ophthalmological and imaging data in 72 patients with NFA treated between 1985 and 1998 with external beam radiation therapy after surgery Clinical follow-up after radiation therapy had to be at least 18 months. RON was defined as a sudden and profound irreversible visual loss affecting the optic nerve or chiasm A review of previously published cases of RON was then performed. In our cohort, no patient had RON. A total of 11 adequately documented series reports of RON were found in the medical literature on radiation-treated NFAs. The incidence of RON in NFA from these series is 0.53% (95% CI, 0.26%-0.96%). An additional 14 single RON cases have been reported, bringing the total of adequately documented RON cases to 25. RON is a rare complication after external beam radiation therapy for NFA.

Adenoma↗
PubMed2004

Angiotensin administration stimulates renal 11 beta-hydroxysteroid dehydrogenase activity in healthy men.

BACKGROUND: We examined whether acute administration of angiotensin modulates the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), the intracellular enzyme catalyzing the interconversion between the hormonally active cortisol and inactive cortisone. METHODS: Twenty-one male healthy subjects were examined after 1 week of a low- and high-salt diet (50 and 200 mmol/day, respectively). Separate infusions of angiotensin I (Ang I) and II (Ang II) were administered, both at rates of 4 and 8 ng/kg/min. The ratios of tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone (THF + allo-THF/THE) and of free cortisol/free cortisone (UFF/UFE) in urine were measured as indices of overall 11 beta HSD set point and activity of renal 11 beta HSD type 2, respectively. Glomerular filtration rate (GFR) was measured by constant infusion of (125)I-iothalamate. RESULTS: Ang I and Ang II infusion dose-dependently increased mean arterial blood pressure (MAP) and plasma aldosterone, and decreased plasma renin activity (PRA) and GFR at both diets. Ang I and Ang II infusion resulted in a dose-dependent decrease in the excretion of UFF, UFE, and of the UFF/UFE ratio at both diets, without changing the urinary (THF + allo-THF)/THE ratio. Salt restriction did not affect these 11 beta HSD variables, but was accompanied by a decrease in UFF and UFE excretion. CONCLUSION: This study suggests that acute angiotensin administration stimulates the activity of 11 beta HSD type 2 in human kidney. Angiotensin might therefore exert a dual effect on the mineralocorticoid receptor (i.e., an indirect agonistic effect by increasing aldosterone availability and a direct or indirect antagonistic effect by stimulation of renal 11 beta HSD type 2 activity).

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2003

Radiation optic neuropathy after external beam radiation therapy for acromegaly: report of two cases.

For diagnosing radiation optic neuropathy (RON) ophthalmological and imaging data were evaluated from 63 acromegalic patients, irradiated between 1967 and 1998. Two patients developed RON: one patient in one optic nerve 10 years and another patient in both optic nerves 5 months after radiation therapy. RON is a rare complication after external beam radiation therapy for acromegaly, which can occur after a considerable latency period.

Acromegaly↗