Publications by authors named "Gert-Jan van de Geijn"

36 Publications

Short-term and long-term effect of a high-intensity pulmonary rehabilitation programme in obese patients with asthma: a randomised controlled trial.

Eur Respir J 2020 07 2;56(1). Epub 2020 Jul 2.

Dept of Pulmonology Franciscus Gasthuis & Vlietland Rotterdam The Netherlands.

Objective: To determine the short-term and long-term effects of a high intensity pulmonary rehabilitation programme on asthma control, body composition, lung function and exercise capacity in obese asthma patients.

Methods: Patients with obesity (body mass index (BMI)≥30 kg·m) and suboptimal controlled asthma (Asthma Control Questionnaire (ACQ)≥0.75) were randomly assigned to a 3-month pulmonary rehabilitation programme (PR only), pulmonary rehabilitation programme with the use of an internet based self-management support programme (PR+SMS) or usual care. The pulmonary rehabilitation programme included high-intensity interval training, nutritional intervention and psychological group sessions. Patients in the usual care group were advised to lose weight and to exercise. The primary outcome was the difference of change of ACQ between PR only and PR+SMS after 3 months. Total follow-up was 12 months.

Results: 34 patients were included in the study (14 PR only, nine PR+SMS, 11 control). Compared with patients in usual care, patients in the PR only group had a significant reduction in BMI and significant improvements in asthma control, exercise capacity and aerobic capacity after 3 months. These improvements persisted during 12 months of follow-up. No difference in ACQ between PR+SMS and PR only groups was observed. However, users of the SMS programme had a significantly lower BMI after 12 months compared with subjects in the PR only group.

Conclusion: A high-intensity pulmonary rehabilitation programme provides sustained improvements in asthma control, body composition and exercise capacity in obese asthmatics that are not optimally controlled and, therefore, should be considered in the treatment of these patients.
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http://dx.doi.org/10.1183/13993003.01820-2019DOI Listing
July 2020

A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus.

Diabetes Obes Metab 2020 05 27;22(5):807-816. Epub 2020 Jan 27.

Department of Internal Medicine, Center for Diabetes and Vascular Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands.

Aim: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear.

Material And Methods: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated.

Results: Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed.

Conclusions: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants.
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http://dx.doi.org/10.1111/dom.13960DOI Listing
May 2020

The effect of sex and menopause on carotid intima-media thickness and pulse wave velocity in morbid obesity.

Eur J Clin Invest 2019 Jul 6;49(7):e13118. Epub 2019 May 6.

Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands.

Background: Women are relatively protected from cardiovascular disease compared with men. Since morbid obesity is an independent risk factor for cardiovascular disease, the current study investigated whether the association between sex and cardiovascular risk factors and outcomes can be demonstrated in subjects suffering from morbid obesity.

Materials And Methods: Two hundred subjects enrolled in a study on cardiovascular risk factors in morbid obesity underwent extensive laboratory screening, carotid intima-media thickness (cIMT) and pulse wave velocity (PWV) measurements. Gender differences were analysed using univariate and multivariable linear regression models. In addition, the effect of menopause on cIMT and PWV was analysed. Results of these models were reported as B coefficients with 95% confidence intervals.

Results: The group consisted of 52 men and 148 women, with a mean age of 41 (±11.8) years and a mean body mass index (BMI) of 42.7 (±5.2) kg/m . Both, cIMT and PWV were significantly higher in men than in women, although the difference in cIMT disappeared after adjustment for covariables such as waist circumference, age, high-density lipoprotein cholesterol and mean arterial pressure. PWV was associated with sex after adjustments for covariables in morbidly obese patients. Postmenopausal women had significantly increased cIMT and PWV when compared with premenopausal women.

Conclusion: Sex differences in PWV persist in subjects suffering from morbid obesity. However, no difference was found in cIMT between morbidly obese men and women after adjustment for classic cardiovascular risk factors. Premenopausal morbidly obese women are protected for cardiovascular disease when compared with postmenopausal morbidly obese women.
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http://dx.doi.org/10.1111/eci.13118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617718PMC
July 2019

Mannose binding lectin and prediction of risk for chemotherapy induced febrile neutropenia in patients with a solid tumor.

Cancer Invest 2019 25;37(3):156-162. Epub 2019 Mar 25.

a Department of Internal Medicine , Franciscus Gasthuis , Rotterdam , The Netherlands.

Mannose-binding lectin (MBL) - deficient patients who undergo chemotherapy for a solid tumor might have an increased risk developing febrile neutropenia (FN). We investigated in a prospective cohort study relations between MBL-serum levels and polymorphisms in MBL promotor genotypes (-550H/L and -221X/Y) on incidence and severity of FN. Risk of FN was 17.9% in MBL-deficient and 22.5% in MBL-sufficient patients (RR = 0.796, p = 0.45). Median MBL serum levels at baseline were respectively 1.39 µg/mL and 1.09 µg/mL (p = 0.92) in patients with and without FN. In conclusion, serum MBL and MBL genotypes (-550H/L and -221X/Y) do not determine the risk for developing FN.
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http://dx.doi.org/10.1080/07357907.2019.1582660DOI Listing
April 2019

Effect of a treat-to-target intervention of cardiovascular risk factors on subclinical and clinical atherosclerosis in rheumatoid arthritis: a randomised clinical trial.

Ann Rheum Dis 2019 03 4;78(3):335-341. Epub 2019 Jan 4.

Department of Internal Medicine, Center for Diabetes and Vascular Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.

Background: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD). No long-term intervention trials on CVD risk factors have been published, and a debate on the efficacy of controlling traditional risk factors in RA is ongoing. We aimed to evaluate a treat-to-target approach versus usual care regarding traditional CVD risk factors in patients with RA.

Methods: In this open-label, randomised controlled trial, patients with RA aged <70 years without prior CVD or diabetes mellitus were randomised 1:1 to either a treat-to-target approach or usual care of traditional CVD risk factors. The primary outcome was defined as change in carotid intima media thickness (cIMT) over 5 years, and the secondary outcome was a composite of first occurrence of fatal and non-fatal cardiovascular events.

Results: A total of 320 patients (mean age 52.4 years; 69.7% female) with RA underwent randomisation and 219 patients (68.4%) completed 5 years of follow-up. The mean cIMT progression was significantly reduced in the treat-to-target group compared with usual care (0.023 [95% CI 0.011 to 0.036] mm vs 0.045 [95% CI 0.030 to 0.059] mm; p=0.028). Cardiovascular events occurred in 2 (1.3%) of the patients in the treat-to-target group vs 7 (4.7%) in those receiving usual care (p=0.048 by log-rank test).

Conclusion: This study provides evidence on the benefit of a treat-to-target approach of traditional CVD risk factors for primary prevention in patients with well-treated RA.

Trial Registration Number: NTR3873.
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http://dx.doi.org/10.1136/annrheumdis-2018-214075DOI Listing
March 2019

Cross-sectional and prospective follow-up study to detect early signs of cardiac dysfunction in obesity: protocol of the CARDIOBESE study.

BMJ Open 2018 12 5;8(12):e025585. Epub 2018 Dec 5.

Department of Cardiology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.

Introduction: In view of the increasing occurrence of both obesity and heart failure, a growing overlap of these two clinical entities in the near future is expected. Significant advances in our understanding of the pathophysiological consequences of obesity for the cardiovascular system have been made over the past two decades. However, to optimise management and treatment of obesity patients, further research is required to improve early identification of cardiac dysfunction in obesity and to gain insight in the underlying pathophysiology. The CARdiac Dysfunction In OBesity - Early Signs Evaluation (CARDIOBESE) study has been designed to address these issues.

Methods And Analysis: CARDIOBESE is a cross-sectional multicentre study of 100 obesity patients scheduled for bariatric surgery (body mass index (BMI) ≥35 kg/m) without known cardiovascular disease, and 50 age-matched and gender-matched non-obese controls (BMI <30 kg/m). Echocardiography, blood and urine biomarkers and Holter monitoring will be used to identify parameters that are able to show cardiac dysfunction at a very early stage in obesity patients (). Furthermore, a prospective follow-up study of obesity patients before and 1 year after bariatric surgery will be done to gain insight in the pathophysiology of obesity causing cardiac dysfunction ().

Ethics And Dissemination: The study was approved by the Medical Ethics Committee Toetsingscommissie Wetenschappelijk Onderzoek Rotterdam e.o. (TWOR). Inclusion of patients and controls is almost complete. Analyses of the investigations are currently being performed, and dissemination through peer-reviewed publications and conference presentations is expected from the first quarter of 2019. By identifying early markers of cardiac dysfunction in obesity, and by understanding the underlying pathophysiology of the abnormalities of these markers, the CARDIOBESE study may provide guidance for risk stratification, monitoring and treatment strategies for obesity patients.
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http://dx.doi.org/10.1136/bmjopen-2018-025585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286494PMC
December 2018

MOLGENIS research: advanced bioinformatics data software for non-bioinformaticians.

Bioinformatics 2019 03;35(6):1076-1078

Genomics Coordination Center, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Motivation: The volume and complexity of biological data increases rapidly. Many clinical professionals and biomedical researchers without a bioinformatics background are generating big '-omics' data, but do not always have the tools to manage, process or publicly share these data.

Results: Here we present MOLGENIS Research, an open-source web-application to collect, manage, analyze, visualize and share large and complex biomedical datasets, without the need for advanced bioinformatics skills.

Availability And Implementation: MOLGENIS Research is freely available (open source software). It can be installed from source code (see http://github.com/molgenis), downloaded as a precompiled WAR file (for your own server), setup inside a Docker container (see http://molgenis.github.io), or requested as a Software-as-a-Service subscription. For a public demo instance and complete installation instructions see http://molgenis.org/research.
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http://dx.doi.org/10.1093/bioinformatics/bty742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419911PMC
March 2019

Discrepancies Between BMI and Classic Cardiovascular Risk Factors.

Obes Surg 2018 11;28(11):3484-3491

Department of Internal Medicine, Franciscus Gasthuis, PO Box 10900, 3004 BA, Rotterdam, The Netherlands.

Background: Obesity is related to increased cardiovascular risk. It is unknown whether increasing levels of obesity also increase levels of cardiovascular risk factors and systemic inflammation. This study describes the relationship between classic cardiovascular risk factors and inflammatory markers with BMI in a group of obese and non-obese subjects.

Materials And Methods: Obese subjects (BMI ≥ 30 kg/m; n = 576; mean ± SD BMI 43.8 ± 7.58 kg/m) scheduled for bariatric surgery were included. The reference population consisted of non-obese volunteers (BMI < 30 kg/m; n = 377, BMI 25.0 ± 2.81 kg/m). The relationship between BMI quintiles and the levels of cardiovascular risk factors was analyzed. Adipose tissue volumetry was performed in 42 obese subjects using abdominal CT scans.

Results: The obese group included more women and subjects with type 2 diabetes mellitus, hypertension, and current smoking behavior. In obese subjects, HDL-C and triglycerides decreased with increasing BMI. Systolic and diastolic blood pressure, total cholesterol, LDL-C, and apoB were not related to BMI in the obese group, in contrast to the non-obese group. Inflammatory markers CRP, leukocyte count, and serum complement C3 increased with increasing BMI in the obese group, while these relations were less clear in the non-obese group. The subcutaneous adipose tissue surface was positively correlated to BMI, while no correlation was observed between BMI and visceral adipose tissue.

Conclusions: Markers of inflammation are strongest related to BMI in obese subjects, most likely due to increased adipose tissue mass, while cardiovascular risk factors do not seem to deteriorate above a certain BMI level. Limited expansion capacity of visceral adipose tissue may explain these findings.
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http://dx.doi.org/10.1007/s11695-018-3359-9DOI Listing
November 2018

Contribution of Type 2 Diabetes Mellitus to Subclinical Atherosclerosis in Subjects with Morbid Obesity.

Obes Surg 2018 08;28(8):2509-2516

Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands.

Introduction: Type 2 diabetes mellitus (T2DM) and obesity are both related to increased risk of cardiovascular disease and mortality. Early atherosclerotic vascular changes can be detected by non-invasive tests like carotid artery intima-media thickness (cIMT) and pulse wave velocity (PWV). Both cIMT and PWV are significantly impaired in T2DM patients and in obese patients, but the additional effect of T2DM on these vascular measurements in obese subjects has not been evaluated.

Methods: Two hundred morbidly obese patients with or without T2DM were enrolled in a prospective cohort study and underwent extensive laboratory testing, including cIMT and PWV measurements. The cohort was divided into a group with and a group without T2DM.

Results: Within this cohort, 43 patients (21.5%) were diagnosed with T2DM. These patients were older and had more often (a history of) hypertension as compared to patients without T2DM. HbA1c levels were significantly increased, while LDL cholesterol was significantly lower and the use of statins higher than in non-diabetic participants. cIMT and PWV were significantly increased in subjects suffering from T2DM. The variability in cIMT and PWV was related to differences in age and systolic blood pressure, but not to the presence of T2DM.

Conclusion: While T2DM negatively affects the vasculature in morbid obesity, hypertension and age seem to be the major risk factors, independent from the presence of T2DM.

Clinical Trial Registration: Dutch Trial Register NTR5172 .
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http://dx.doi.org/10.1007/s11695-018-3196-xDOI Listing
August 2018

Progression of subclinical atherosclerosis in subjects with rheumatoid arthritis and the metabolic syndrome.

Atherosclerosis 2018 04 17;271:84-91. Epub 2018 Feb 17.

Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Kleiweg 500, 3045, PM, Rotterdam, The Netherlands.

Background And Aims: Rheumatoid arthritis (RA) has been associated with an increased risk of atherosclerosis. We aimed to evaluate the progression of carotid intima media thickness (cIMT) in RA patients subject to a cardiovascular treat-to-target intervention. In addition, the presence of the metabolic syndrome (MetS) on cIMT outcomes was evaluated.

Methods: We performed a cohort analysis of FRANCIS, in which RA patients ≤70 years without CVD or diabetes mellitus were randomized for either a treat-to-target intervention or usual care concerning CVD risk factors. MetS was scored at baseline.

Results: Three-year data was available in 212 well-controlled RA patients. The treat-to-target intervention resulted in a lower cIMT progression over three years compared to the usual care. However, there was no difference in cIMT at three years between groups. MetS was present in 40.1% of RA patients. Baseline cIMT was significantly higher in RA patients with MetS compared to those without (0.619 (0.112) versus 0.557 (0.104) mm; p < 0.001). After three years, cIMT progression was comparable (0.043 (0.071) versus 0.043 (0.072) mm; p = 0.96). In RA patients with MetS, the presence of plaques increased over three years from 12.9% to 23.5% (p = 0.01). The type of intervention had no effect on cIMT progression in RA patients with MetS. However, in subjects without MetS, treat-to-target resulted in a lower progression.

Conclusions: RA patients with MetS showed an increased CVD risk profile based on both a higher prevalence of CVD risk factors and structural vascular changes. A treat-to-target approach of CVD risk factors reduced cIMT progression only in RA patients without MetS.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.02.019DOI Listing
April 2018

Evidence for increased chylomicron remnants in rheumatoid arthritis.

Eur J Clin Invest 2018 Feb 8;48(2). Epub 2018 Jan 8.

Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.

Background: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis.

Methods: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage.

Results: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti-CCP positive compared to the lowest tertile.

Conclusion: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients.
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http://dx.doi.org/10.1111/eci.12873DOI Listing
February 2018

Erythrocyte-bound apolipoprotein B in atherosclerosis and mortality.

Eur J Clin Invest 2017 Apr 25;47(4):289-296. Epub 2017 Feb 25.

Department of Internal Medicine, Centre for Diabetes and Vascular Medicine, Franciscus Gasthuis, Rotterdam, the Netherlands.

Background: The binding of apolipoprotein (apo) B-containing lipoproteins to circulating erythrocytes (ery-apoB) is associated with a decreased prevalence of atherosclerosis. In this study, we evaluated ery-apoB as a possible prognostic factor in cardiovascular events and all-cause mortality, in a prospective cohort study.

Materials And Methods: Ery-apoB was measured by flow cytometry in subjects with and without cardiovascular disease (CVD). The primary endpoint was the cardiovascular event rate. Secondary endpoints were all-cause mortality and the combined endpoint of all-cause mortality and cardiovascular events (any event rate). A Cox regression analysis with univariate and multivariate analyses and Kaplan-Meier survival analysis was performed.

Results: Follow-up data were available of 384 subjects. Subjects were divided according to high (> 2·0 au, n = 60), intermediate (0·2-2·0 au, n = 274) or low (< 0·2 au, n = 50) ery-apoB. Median follow-up was 1767 days (IQR 1564-2001). In univariate analysis, low ery-apoB was associated with increased all-cause mortality [HR 9·9 (1·2-79·0), P = 0·031] and any event rate [HR 3·4 (95% CI 1·3-8·7), P = 0·012]. In a Cox regression analysis, only a history of CVD was significantly associated with any event rate [HR 3·6 (1·6-8·0), P = 0·002], while low ery-apoB showed a trend [HR 2·4 (0·9-6·4), P = 0·07]. In a subgroup analysis, in subjects with a history of CVD, ery-apoB was significantly associated with all-cause mortality (log rank P = 0·021) and any event rate (log rank P = 0·009).

Conclusions: Low ery-apoB is associated with increased mortality and cardiovascular risk, especially in patients with a prior history of CVD. These subjects may benefit from more aggressive secondary prevention treatment.
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http://dx.doi.org/10.1111/eci.12728DOI Listing
April 2017

Effect of a Single Dose of Vitamin D3 on Postprandial Arterial Stiffness and Inflammation in Vitamin D-Deficient Women.

J Clin Endocrinol Metab 2017 Mar;102(3):992-1000

Departments of Internal Medicine, Center for Diabetes and Vascular Medicine.

Context: Cholecalciferol (vitamin D3) improves vascular function and inflammation, potentially providing an explanation for the proposed cardiovascular protection of vitamin D.

Objective: We investigated whether cholecalciferol supplementation reduces postprandial arterial dysfunction and inflammation.

Design: Randomized, 1:1, double-blind trial.

Setting: Diabetes and Vascular Center, Franciscus Gasthuis, Rotterdam, The Netherlands.

Patients: Twenty-four healthy, premenopausal, overweight or obese, vitamin D-deficient women.

Interventions: A single high (300,000 IU) or low dose (75,000 IU) of cholecalciferol.

Main Outcome Measures: The effect of low- and high-dose cholecalciferol on postprandial leukocyte activation markers, pulse wave velocity (PWV), and augmentation index (AIx) during an oral fat loading test, expressed as area under the curve (AUC).

Results: High- and low-dose supplementation increased vitamin D by 163% ± 134% (P < 0.001) and 66% ± 59% (P < 0.001), respectively. Monocyte CD11b-AUC slightly increased after low but not high dose (6% ± 2%, P = 0.012, and 4% ± 1%, P = 0.339, respectively). There were no significant effects on postprandial PWV or AIx by high- or low-dose vitamin D. Fasting complement component 3 (C3) levels decreased by 5.9% (P = 0.004) in the high-dose group and by 4.0% (P = 0.018) in the low-dose group.

Conclusion: A single dose of vitamin D does not seem to reduce arterial stiffness and leukocyte activation in overweight, vitamin D-deficient women. Vitamin D may decrease fasting C3. Possibly, higher vitamin D concentrations may be needed to decrease inflammation and improve vascular function in overweight or obese vitamin D-deficient women.
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http://dx.doi.org/10.1210/jc.2016-3394DOI Listing
March 2017

Leucocyte-bound apolipoprotein B in the circulation is inversely associated with the presence of clinical and subclinical atherosclerosis.

Eur J Clin Invest 2016 Aug 8;46(8):690-7. Epub 2016 Jul 8.

Department of Internal Medicine, Center for Diabetes and Vascular Medicine, St. Franciscus Gasthuis, Rotterdam, The Netherlands.

Background: Atherosclerosis is a pro-inflammatory condition, in which leucocyte activation plays an important role. The interaction between circulating leucocytes and apolipoprotein (apo) B-containing lipoproteins results in pro-inflammatory changes of these cells. We aimed to evaluate the relationship between apo B bound to circulating leucocytes and atherosclerosis.

Methods: Apo B on circulating leucocytes was measured by flow cytometry in subjects with and without cardiovascular disease (CVD), expressed as mean fluorescent intensity in arbitrary units (au). Carotid intima-media thickness (cIMT) was measured using B-mode ultrasound. Data are given as median (interquartile range).

Results: A total of 396 subjects were included, of whom 183 had a history of CVD. Compared to subjects without CVD, patients with CVD had lower apo B bound to neutrophils (12·7 au (9·8-16·2) and 14·2 au (10·1-17·5), respectively, P = 0·038) and to monocytes (2·5 au (1·7-3·1) and 2·7 (1·9-3·6) au, respectively, P = 0·025). No differences were found for lymphocyte-bound apo B. Neutrophil- and monocyte-bound apo B were inversely correlated with cIMT (Spearman's rho: -0·123, P = 0·017 and -0·108, P = 0·035, respectively). Both monocyte- and neutrophil-bound apo B were inversely associated with different factors related to the metabolic syndrome, such as body mass index, triglycerides and complement C3. There was a positive association between erythrocyte-bound apo B and apo B bound to each of the leucocyte classes, possibly reflecting a similar mechanism. Discontinuation of statins in 54 subjects did not influence leucocyte-bound apo B.

Conclusion: Unexpectedly, the presence of noninternalized apo B-containing lipoproteins on circulating neutrophil and monocyte membranes may represent a protective mechanism against atherosclerosis.
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http://dx.doi.org/10.1111/eci.12650DOI Listing
August 2016

Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis.

Rheumatology (Oxford) 2016 07 23;55(7):1210-6. Epub 2016 Mar 23.

Department of Internal Medicine.

Objective: To investigate the prevalence of underdiagnosis and undertreatment of traditional cardiovascular risk factors in RA patients.

Methods: RA patients ⩽70 years of age without cardiovascular disease (CVD) or diabetes mellitus were included. Systolic blood pressure and a fasting lipid profile were measured. The 10-year CVD risk was estimated using the Dutch Cardiovascular Risk Management (CVRM) guideline and EULAR modifications of the Systemic Coronary Risk Evaluation tables.

Results: A total of 327 patients were included (female gender: 68%). The mean age was 53 (11) years [mean (s.d.)]. The median disease duration was 7 years (inter quartile range: 2-14 years). According to the CVRM guideline, 52% of the patients had a CVD risk ⩾20% and according to the EULAR guidelines, 18% of the patients had a CVD risk ≥ 20%. Low-density lipoprotein cholesterol (LDL-C) >2.5 mmol/l was found in >80% of the patients with a CVD risk ⩾10% as estimated by both the CVRM and EULAR guidelines, and 32-42% of the patients with a CVD risk ⩾10% had a systolic blood pressure >140 mmHg, depending on the risk model used. Statins were used in 6% and antihypertensives in 23-25%, and 50-86% of these patients did not reach the recommended treatment targets.

Conclusion: Regardless of the adapted risk assessment model used, untreated hypertension and hypercholesterolaemia were frequently found in RA patients with increased CVD risk. Treatment of these cardiovascular risk factors deserves more attention in RA.

Trial Registration: The Dutch Trial Register, www.trialregister.nl, NTR3873.
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http://dx.doi.org/10.1093/rheumatology/kew039DOI Listing
July 2016

In vivo evidence for chylomicrons as mediators of postprandial inflammation.

Atherosclerosis 2015 Dec 23;243(2):540-5. Epub 2015 Oct 23.

Department of Internal Medicine, Center for Diabetes and Vascular Medicine, Rotterdam, The Netherlands. Electronic address:

Background And Aims: The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers.

Methods: Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h).

Results: Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression.

Conclusion: This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.025DOI Listing
December 2015

Association of Cardiovascular Risk Factors with Carotid Intima Media Thickness in Patients with Rheumatoid Arthritis with Low Disease Activity Compared to Controls: A Cross-Sectional Study.

PLoS One 2015 20;10(10):e0140844. Epub 2015 Oct 20.

Department of Internal Medicine, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.

Objectives: Rheumatoid arthritis (RA) has been identified as an independent cardiovascular risk factor. The importance of risk factors such as hypertension and hyperlipidemia in the generation of atherosclerosis in RA patients is unclear. This study analyzed clinical parameters associated with carotid intima media thickness (cIMT) in patients with RA.

Methods: Subjects with RA and healthy controls without RA, both without known cardiovascular disease, were included. Participants underwent a standard physical examination and laboratory measurements including a lipid profile. cIMT was measured semi-automatically by ultrasound.

Results: In total 243 RA patients and 117 controls were included. The median RA disease duration was 7 years (IQR 2-14 years). The median DAS28 was 2.4 (IQR 1.6-3.2) and 114 (50.4%) of the RA patients were in remission. The presence of RA and cIMT were not associated (univariate analysis). Multivariable regression analysis showed that cIMT in RA patients was associated with age (B = 0.006, P<0.001) and systolic blood pressure (B = 0.003, P = 0.003). In controls, cIMT was associated with age (B = 0.006, P<0.001) and smoking (B = 0.097, P = 0.001).

Conclusion: cIMT values were similar between RA patients and controls. Hypertension was strongly associated with cIMT in RA patients. After adjustment, no association between cIMT and specific RA disease characteristics was found in this well treated RA cohort.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617300PMC
June 2016

Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma.

Thorax 2015 Jul 30;70(7):659-67. Epub 2015 Apr 30.

Department of Pulmonology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.

Background: The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear.

Methods: A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS-A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months.

Results: Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS-A group FEV1, functional residual capacity, total lung capacity improved, whereas FEV1/FVC only improved in the BS-A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD20 improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R5-R20 improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R5-R20 between BS+A and BS-A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group.

Conclusions: Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity.

Trial Registration Number: 3204.
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http://dx.doi.org/10.1136/thoraxjnl-2014-206712DOI Listing
July 2015

Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls.

Metabolism 2015 Feb 16;64(2):213-7. Epub 2014 Oct 16.

Department of Internal Medicine, Center for Diabetes and Cardiovascular Risk Management, Sint Franciscus Gasthuis, Rotterdam, the Netherlands.

Background: Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity.

Methods: Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC).

Results: 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023).

Conclusions: These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions.
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http://dx.doi.org/10.1016/j.metabol.2014.10.011DOI Listing
February 2015

Differential complement activation pathways promote C3b deposition on native and acetylated LDL thereby inducing lipoprotein binding to the complement receptor 1.

J Biol Chem 2014 Dec 27;289(51):35421-30. Epub 2014 Oct 27.

From the Departments of Internal Medicine, Diabetes and Vascular Center,

Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM, and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo up-regulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B-containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1.
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http://dx.doi.org/10.1074/jbc.M114.573840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271227PMC
December 2014

A new flow cytometric method for differential cell counting in ascitic fluid.

Cytometry B Clin Cytom 2016 11 21;90(6):506-511. Epub 2014 Mar 21.

Department of Clinical Chemistry (KCHL), Sint Franciscus Gasthuis, 3045 PM, Rotterdam, The Netherlands.

Background: Cell counts in bodyfluids such as ascitic fluid can be difficult to perform and report rapidly. The current gold standard for cell counting in body fluids is a suitable automated cell counter or a manual counting chamber, combined with differential counting on a cytospin. This technique has several disadvantages, so we designed a new flow cytometric test for cell counting in ascites. We compared this with an automatic cell counter (LH750, Beckman Coulter) and manual counting of cytospins.

Methods: Ascitic samples (n = 53) from 38 patients were studied. Polymorphonuclear neutrophils (PMN), lymphocytes, eosinophils, and macrophages were defined by flow cytometry. We compared this with our reference method: the absolute cell concentration calculated from the leukocyte concentration of the LH750 combined with a differential cell count performed manually on a cytospin.

Results: The outcomes of validation experiments (linearity, reproducibility, and detection limit) of the flow cytometric assay prove it is well suited for cell counting in ascitic fluid.

Conclusions: Based on analytical performance, flow cytometry is suited for cell counting in ascitic fluid. An ascitic fluid cell count is frequently ordered to detect spontaneous bacterial peritonitis (SBP). If the PMN count is ≥250 cells/mm , SBP is highly suspected. Using our reference method, we calculated the sensitivities and specificities to detect ≥250 PMN cells/mm for the LH750 (100% and 65%, respectively) and flow cytometric assay (100%, 100%). As flow cytometry is easier and faster we recommend this method for rapid cell counting in ascitic fluid. © 2014 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21171DOI Listing
November 2016

A new flow cytometric method for differential cell counting in ascitic fluid.

Cytometry B Clin Cytom 2014 Feb 27. Epub 2014 Feb 27.

Department of Clinical Chemistry (KCHL), Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands.

Background: Cell counts in bodyfluids such as ascitic fluid can be difficult to perform and report rapidly. The current gold standard for cell counting in body fluids is a suitable automated cell counter or a manual counting chamber, combined with differential counting on a cytospin. This technique has several disadvantages, so we designed a new flow cytometric test for cell counting in ascites. We compared this with an automatic cell counter (LH750, Beckman Coulter) and manual counting of cytospins. Methods: Ascitic samples (n=53) from 38 patients were studied. Polymorphonuclear neutrophils (PMN), lymphocytes, eosinophils, and macrophages were defined by flow cytometry. We compared this with our reference method: the absolute cell concentration calculated from the leukocyte concentration of the LH750 combined with a differential cell count performed manually on a cytospin. Results: The outcomes of validation experiments (linearity, reproducibility and detection limit) of the flow cytometric assay prove it is well suited for cell counting in ascitic fluid. Conclusions: Based on analytical performance, flow cytometry is suited for cell counting in ascitic fluid. An ascitic fluid cell count is frequently ordered to detect spontaneous bacterial peritonitis (SBP). If the PMN count is ≥ 250 cells/mm , SBP is highly suspected. Using our reference method, we calculated the sensitivities and specificities to detect ≥ 250 PMN cells/mm for the LH750 (100% and 65% respectively) and flow cytometric assay (100 %, 100 %). As flow cytometry is easier and faster we recommend this method for rapid cell counting in ascitic fluid. © 2014 Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cytob.21171DOI Listing
February 2014

Automated screening for myelodysplastic syndromes through analysis of complete blood count and cell population data parameters.

Am J Hematol 2014 Apr 13;89(4):369-74. Epub 2014 Mar 13.

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania.

The diagnosis of myelodysplastic syndromes (MDS) requires a high clinical index of suspicion to prompt bone marrow studies as well as subjective assessment of dysplastic morphology. We sought to determine if data collected by automated hematology analyzers during complete blood count (CBC) analysis might help to identify MDS in a routine clinical setting. We collected CBC parameters (including those for research use only and cell population data) and demographic information in a large (>5,000), unselected sequential cohort of outpatients. The cohort was divided into independent training and test groups to develop and validate a random forest classifier that identifies MDS. The classifier effectively identified MDS and had a receiver operating characteristic area under the curve (AUC) of 0.942. Platelet distribution width and the standard deviation of red blood cell distribution width were the most discriminating variables within the classifier. Additionally, a similar classifier was validated with an additional, independent set of >200 patients from a second institution with an AUC of 0.93. This retrospective study demonstrates the feasibility of identifying MDS in an unselected outpatient population using data routinely collected during CBC analysis with a classifier that has been validated using two independent data sets from different institutions.
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http://dx.doi.org/10.1002/ajh.23643DOI Listing
April 2014

Erythrocyte-bound apolipoprotein B in relation to atherosclerosis, serum lipids and ABO blood group.

PLoS One 2013 19;8(9):e75573. Epub 2013 Sep 19.

Department of Internal Medicine, Diabetes and Vascular Center, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.

Introduction: Erythrocytes carry apolipoprotein B on their membrane, but the determining factors of erythrocyte-bound apolipoprotein B (ery-apoB) are unknown. We aimed to explore the determinants of ery-apoB to gain more insight into potential mechanisms.

Methods: Subjects with and without CVD were included (N = 398). Ery-apoB was measured on fresh whole blood samples using flow cytometry. Subjects with ery-apoB levels ≤ 0.20 a.u. were considered deficient. Carotid intima media thickness (CIMT) was determined as a measure of (subclinical) atherosclerosis.

Results: Mean ery-apoB value was 23.2% lower in subjects with increased CIMT (0.80 ± 0.09 mm, N = 140) compared to subjects with a normal CIMT (0.57 ± 0.08 mm, N = 258) (P = 0.007, adjusted P<0.001). CIMT and ery-apoB were inversely correlated (Spearman's r: -0.116, P = 0.021). A total of 55 subjects (13.6%) were considered ery-apoB deficient, which was associated with a medical history of CVD (OR: 1.86, 95% CI 1.04-3.33; adjusted OR: 1.55; 95% CI 0.85-2.82). Discontinuation of statins in 54 subjects did not influence ery-apoB values despite a 58.4% increase in serum apolipoprotein B. Subjects with blood group O had significantly higher ery-apoB values (1.56 ± 0.94 a.u.) when compared to subjects with blood group A (0.89 ± 1.15 a.u), blood group B (0.73 ± 0.1.12 a.u.) or blood group AB (0.69 ± 0.69 a.u.) (P-ANOVA = 0.002).

Conclusion: Absence or very low values of ery-apoB are associated with clinical and subclinical atherosclerosis. While serum apolipoprotein B is not associated with ery-apoB, the ABO blood group seems to be a significant determinant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777967PMC
June 2014

Underdiagnosis and overdiagnosis of asthma in the morbidly obese.

Respir Med 2013 Sep 10;107(9):1356-64. Epub 2013 Jun 10.

Sint Franciscus Gasthuis, Department of Pulmonology, Kleiweg 500, 3045 PM Rotterdam, The Netherlands.

Background: The prevalence of obesity and asthma has increased concurrently over the last decades, suggesting a link between obesity and asthma. However, asthma might not be adequately diagnosed in this population.

Aim: To investigate whether not only overdiagnosis but also underdiagnosis of asthma is present in an obese population.

Methods: Morbidly obese subjects with or without physician-diagnosed asthma were recruited from a pre-operative screening programme for bariatric surgery, and were characterized using an extensive diagnostic algorithm.

Results: 473 subjects were screened; 220 met inclusion criteria, and 86 agreed to participate. Among the 32 participating subjects who had a physician diagnosis of asthma, reversible airway obstruction and/or bronchial hyperresponsiveness could only be detected in 19 patients (59%, 95% CI [0.41-0.76]), whereas in 13 patients (41%, 95% CI [0.24-0.50]) the diagnosis of asthma could not be confirmed (overdiagnosis). In contrast, in the remaining 54 patients, 17 (31%, 95% CI [0.20-0.46]) were newly diagnosed with asthma (underdiagnosis).

Conclusion: Besides overdiagnosis, there is also substantial underdiagnosis of asthma in the morbidly obese. Symptoms could be incorrectly ascribed to either obesity or asthma, and therefore also in the morbidly obese the diagnosis of asthma should also be based on pulmonary function testing.
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http://dx.doi.org/10.1016/j.rmed.2013.05.007DOI Listing
September 2013

Systemic inflammation and lung function impairment in morbidly obese subjects with the metabolic syndrome.

J Obes 2013 24;2013:131349. Epub 2013 Feb 24.

Department of Pulmonology, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM Rotterdam, The Netherlands.

Background: Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment.

Methods: This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria.

Results: A total of 452 patients were included. Patients with the metabolic syndrome (n = 293) had significantly higher blood monocyte (mean 5.3 versus 4.9, P = 0.044) and eosinophil percentages (median 1.0 versus 0.8, P = 0.002), while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P = 0.032). Blood eosinophils were associated with FEV1/FVC ratio (adj. B -0.113, P = 0.018).

Conclusion: Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.
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http://dx.doi.org/10.1155/2013/131349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595660PMC
July 2013

Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas.

PLoS One 2012 28;7(8):e43952. Epub 2012 Aug 28.

Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent ~3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429439PMC
February 2013

Erythrocyte-associated apolipoprotein B and its relationship with clinical and subclinical atherosclerosis.

Eur J Clin Invest 2012 Apr 13;42(4):365-70. Epub 2011 Sep 13.

Department of Internal Medicine, Sint Franciscus Gasthuis Rotterdam, Rotterdam, The Netherlands.

Background: Apolipoprotein (apo) B-containing lipoproteins are closely linked to atherogenesis. These lipoproteins are transported in plasma and are also associated with blood leucocytes. Our aim was to investigate whether apoB-containing lipoproteins are also present on the surface of erythrocytes and investigate the relationship with the presence of atherosclerosis in a cross-sectional study.

Materials And Methods: Erythrocyte-bound apoB (ery-apoB) was measured by flowcytometry in subjects with (CAD+) and without coronary artery disease (CAD-), based on coronary angiography or on a history of cardiovascular disease. Intima media thickness (IMT) measurements were carried out using B-mode ultrasound. The relationship between ery-apoB and clinical and subclinical atherosclerosis was evaluated with binary logistic regression.

Results: A total of 166 subjects were included (40 CAD+ and 126 CAD-). ApoB was detected on freshly isolated erythrocytes (range: 0·1-5·5 au; mean ± SEM 0·86 ± 0·09 au) in all but nine subjects (four CAD+ and five CAD-). Ery-apoB was lower in CAD+ (0·62 ± 0·09 au) compared to CAD- (1·18 ± 0·10 au; P < 0·001). Higher ery-apoB was associated with a lower risk of CAD (adjusted OR: 0·003 (95% CI: 0·001-0·08; P < 0·001), but the protective effect was diminished with increasing age (adjusted OR: 1·10 (95% CI: 1·04-1·16; P < 0·001). IMT was increased in CAD+ subjects (0·77 ± 0·13 mm) compared to CAD- (0·57 ± 0·14 mm; P < 0·001). A significant negative association was found between ery-apoB and IMT (β = -0·214: 95% CI -0·284 to -0·145; P < 0·001). There was no association between ery-apoB and plasma apoB (Pearson's r = -0·45; P = 0·57).

Conclusions: Human erythrocytes carry apoB-containing lipoproteins. Subjects with atherosclerosis have lower ery-apoB. High ery-apoB may be protective against atherosclerosis and may reflect an alternative blood cell-mediated lipoprotein transport system in the circulation, in which these lipoproteins less likely interact with the endothelium.
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http://dx.doi.org/10.1111/j.1365-2362.2011.02591.xDOI Listing
April 2012

Leukoflow: multiparameter extended white blood cell differentiation for routine analysis by flow cytometry.

Cytometry A 2011 Sep 22;79(9):694-706. Epub 2011 Jul 22.

Department of Clinical Chemistry (KCHL), Sint Franciscus Gasthuis, Kleiweg, PM Rotterdam, The Netherlands.

Differential white blood cell count (dWBC) is a frequently used diagnostic tool. For most patient samples an automated blood counter produces a five-part differential count. If this dWBC does not meet pre-set criteria, microscopic dWBC is performed. Microscopy is labor intensive and requires sustained training of technicians. Inter-observer variation and statistical variation are significant, due to limited numbers of cells counted. Flow cytometry is a candidate reference method for dWBC. Advantages are immunological definitions and large number of measured cells. Our goal was to replace (part of) the microscopic dWBC by a flow cytometric dWBC, that gives additional information on blasts, myeloid precursors, and lymphocyte subsets. We designed a cocktail of antibodies (CD4, CD14, CD34, CD16, CD56, CD19, CD45, CD138, CD3, and CD71) combined with a gating strategy and flow cytometric protocol for easy identification of leukocyte populations. This assay, called Leukoflow, requires low sample volume, has few manual handling steps, and a potential turn-around-time shorter than 2 h. We determine percentages and absolute concentrations of at least 13 different cell populations. For quantification of normoblasts a second flow cytometric staining was designed. We compared microscopic dWBC with that of the automated blood counter and Leukoflow for normal and abnormal blood samples. Leukoflow results correlate well with the automated blood counter for leukocytes, neutrophils, eosinophils, monocytes, and lymphocytes. Correlation with manual dWBC is lower. Blast counts reported by Leukoflow suffer less from inter-observer variation compared to manual dWBC. In addition to microscopic or cytometric dWBC-techniques T-lymphocytes, CD4-T-lymphocytes, B-lymphocytes, NK-cells, myeloid progenitors, plasma cells, and blasts are determined by Leukoflow. These populations give potential useful clinical information and are subject for future studies focusing on the additional clinical value. Leukoflow is a highly interesting and promising technique for clinical laboratories.
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http://dx.doi.org/10.1002/cyto.a.21105DOI Listing
September 2011