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author:("van beuren, S")
2.  EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence 
PLoS Pathogens  2014;10(8):e1004326.
Poxviruses contain large dsDNA genomes encoding numerous open reading frames that manipulate cellular signalling pathways and interfere with the host immune response. The NF-κB signalling cascade is an important mediator of innate immunity and inflammation, and is tightly regulated by ubiquitination at several key points. A critical step in NF-κB activation is the ubiquitination and degradation of the inhibitor of kappaB (IκBα), by the cellular SCFβ-TRCP ubiquitin ligase complex. We show here that upon stimulation with TNFα or IL-1β, Orthopoxvirus-infected cells displayed an accumulation of phosphorylated IκBα, indicating that NF-κB activation was inhibited during poxvirus infection. Ectromelia virus is the causative agent of lethal mousepox, a natural disease that is fatal in mice. Previously, we identified a family of four ectromelia virus genes (EVM002, EVM005, EVM154 and EVM165) that contain N-terminal ankyrin repeats and C-terminal F-box domains that interact with the cellular SCF ubiquitin ligase complex. Since degradation of IκBα is catalyzed by the SCFβ-TRCP ubiquitin ligase, we investigated the role of the ectromelia virus ankyrin/F-box protein, EVM005, in the regulation of NF-κB. Expression of Flag-EVM005 inhibited both TNFα- and IL-1β-stimulated IκBα degradation and p65 nuclear translocation. Inhibition of the NF-κB pathway by EVM005 was dependent on the F-box domain, and interaction with the SCF complex. Additionally, ectromelia virus devoid of EVM005 was shown to inhibit NF-κB activation, despite lacking the EVM005 open reading frame. Finally, ectromelia virus devoid of EVM005 was attenuated in both A/NCR and C57BL/6 mouse models, indicating that EVM005 is required for virulence and immune regulation in vivo.
Author Summary
Poxviruses are large dsDNA viruses that are renowned for regulating cellular pathways and manipulating the host immune response, including the NF-κB pathway. NF-κB inhibition by poxviruses is a growing area of interest and this family of viruses has developed multiple mechanisms to manipulate the pathway. Here, we focus on regulation of the NF-κB pathway by ectromelia virus, the causative agent of mousepox. We demonstrate that ectromelia virus is a potent inhibitor of the NF-κB pathway. Previously, we identified a family of four ectromelia virus genes that contain N-terminal ankyrin repeats and a C-terminal F-box domain that interacts with the cellular SCF ubiquitin ligase. Significantly, expression of the ankyrin/F-box protein, EVM005, inhibited NF-κB, and the F-box domain was critical for NF-κB inhibition and interaction with the SCF complex. Ectromelia virus devoid of EVM005 still inhibited NF-κB, indicating that multiple gene products contribute to NF-κB inhibition. Importantly, mice infected with ectromelia virus lacking EVM005 had a robust immune response, leading to viral clearance during infection. The data present two mechanisms, one in which EVM005 inhibits NF-κB activation through manipulation of the host SCF ubiquitin ligase complex, and an additional, NF-κB-independent mechanism that drives virulence.
PMCID: PMC4133408  PMID: 25122471
3.  Towards a measurement instrument for determinants of innovations 
To develop a short instrument to measure determinants of innovations that may affect its implementation.
We pooled the original data from eight empirical studies of the implementation of evidence-based innovations. The studies used a list of 60 potentially relevant determinants based on a systematic review of empirical studies and a Delphi study among implementation experts. Each study used similar methods to measure both the implementation of the innovation and determinants. Missing values in the final data set were replaced by plausible values using multiple imputation. We assessed which determinants predicted completeness of use of the innovation (% of recommendations applied). In addition, 22 implementation experts were consulted about the results and about implications for designing a short instrument.
Eight innovations introduced in Preventive Child Health Care or schools in the Netherlands.
Doctors, nurses, doctor's assistants and teachers; 1977 respondents in total.
The initial list of 60 determinants could be reduced to 29. Twenty-one determinants were based on the pooled analysis of the eight studies, seven on the theoretical expectations of the experts consulted and one new determinant was added on the basis of the experts' practical experience.
The instrument is promising and should be further validated. We invite researchers to use and explore the instrument in multiple settings. The instrument describes how each determinant should preferably be measured (questions and response scales). It can be used both before and after the introduction of an innovation to gain an understanding of the critical change objectives.
PMCID: PMC4195468  PMID: 24951511
implementation; preventive child healthcare; school-based health promotion
4.  High sensitivity of cancer exome-based CD8 T cell neo-antigen identification 
Oncoimmunology  2014;3:e28836.
Recent data suggest that T-cell reactivity against tumor-specific neo-antigens may be central to the clinical efficacy of cancer immunotherapy. The development of personalized vaccines designed to boost T-cell reactivity against patient specific neo-antigens has been proposed largely on the basis of these findings. Work from several groups has demonstrated that novel tumor-specific antigens can be discovered through the use of cancer exome sequencing data, thereby providing a potential pipeline for the development of patient-specific vaccines. Importantly though, it has not been established which fraction of cancer neo-antigens that can be recognized by CD8+ T cells is successfully uncovered with the current exome-based epitope prediction strategies. Here, we use a data set comprising human cancer neo-antigens that was previously identified through the use of unbiased, computational-independent strategies to describe the potential of cancer exome-based neo-antigen discovery. This analysis shows a high sensitivity of exome-guided neo-antigen prediction of approximately 70%. We propose that future research should focus on the analysis and optimization of the specificity of neo-antigen prediction, and should undoubtedly entail the clinical evaluation of patient-specific vaccines with the aim of inducing immunoreactivity against tumor-displayed neo-antigens in a physiologically relevant context.
PMCID: PMC4106163  PMID: 25083320
epitope prediction; immune monitoring; neo-antigens; tumor vaccine; whole exome sequencing
5.  Trends in a Life Threatening Condition: Morbid Obesity in Dutch, Turkish and Moroccan Children in The Netherlands 
PLoS ONE  2014;9(4):e94299.
Morbid obesity can be a life threatening condition. The aim of our study is to assess the trend in morbid obesity in The Netherlands among children of Dutch origin since 1980, and among children of Turkish and Moroccan origin since 1997.
Methods and Findings
Cross-sectional height and weight data of children of Dutch, Turkish and Moroccan origin aged 2–18 years were selected from three national Dutch Growth Studies performed in 1980, 1997 and 2009 (n = 54,814). Extended international (IOTF) cut-offs in childhood were used to define morbid obesity (obesity class II and III combined). The morbidity index for overweight was calculated as the prevalence of morbid obesity divided by the prevalence of overweight. Our study showed that the prevalence of morbid obesity in children of Dutch origin was 0.59% in boys and 0.53% in girls in 2009. Significant upward trends occurred since 1980 and 1997. The prevalence was three to four fold higher in Turkish children compared to Dutch children. The Turkish children also had an upward trend since 1997, but this was only statistically significant in boys. The prevalence of morbid obesity in Moroccan children was two to three fold higher than in Dutch children, but it remained almost stable between 1997 and 2009. The Dutch and Turkish children showed an upward trend in morbidity index for overweight since respectively 1980 and 1997, while the Moroccan children showed a downward trend since 1997. In 2009, children of low educated parents had the highest prevalence rates of morbid obesity; 1.06% in Dutch, 2.11% in Turkish and 1.41% in Moroccan children.
Conclusions and Significance
An upward trend of morbid obesity in Dutch and Turkish children in The Netherlands occurred. Monitoring and reducing the prevalence of childhood morbid obesity is of high importance for these children, health care and the community.
PMCID: PMC3986047  PMID: 24732729
6.  The Fountain of Age: A Remarkable 3D Shape that Portrays Health and Functional Differences among the European Elderly 
There are very few norms to evaluate and monitor the health and functioning of the elderly. This paper proposes a compact spatial representation of 25 health measurements of European citizens older than 50 years. Data from 44,285 unique individuals were obtained from the EU-wide Survey of Health, Ageing and Retirement in Europe(SHARE) data collected in 2004–2007 and were analyzed by homogeneity analysis, a form of non-linear principal components analysis. The resulting configuration of persons shows a remarkable three-dimensional shape that resembles a fountain. The three components explain 13.7, 5.8 and 4.6 percent of the total variation, respectively. Component 1 is driven by age and by the disabilities that come with old age. Component 2 portrays differences in health that are independent of age, with the high scores in relatively good health, given age. Component 3 distinguishes specific types of functional decline from general complaints that impact on daily life. The shape suggests that the elderly keep on maturing as they grow older, actually becoming more diverse as a group. We show how the solution may be used to develop and support profiles for the elderly. Another potential application is to track the individual development of the elderly, thereby objectifying personalized medicine.
PMCID: PMC4025001  PMID: 24736689
elderly; health; homogeneity analysis; SHARE; GOAL profiles; mobility; monitoring; personalized medicine; data reduction
7.  Signatures of mutational processes in human cancer 
Alexandrov, Ludmil B. | Nik-Zainal, Serena | Wedge, David C. | Aparicio, Samuel A.J.R. | Behjati, Sam | Biankin, Andrew V. | Bignell, Graham R. | Bolli, Niccolo | Borg, Ake | Børresen-Dale, Anne-Lise | Boyault, Sandrine | Burkhardt, Birgit | Butler, Adam P. | Caldas, Carlos | Davies, Helen R. | Desmedt, Christine | Eils, Roland | Eyfjörd, Jórunn Erla | Foekens, John A. | Greaves, Mel | Hosoda, Fumie | Hutter, Barbara | Ilicic, Tomislav | Imbeaud, Sandrine | Imielinsk, Marcin | Jäger, Natalie | Jones, David T.W. | Jones, David | Knappskog, Stian | Kool, Marcel | Lakhani, Sunil R. | López-Otín, Carlos | Martin, Sancha | Munshi, Nikhil C. | Nakamura, Hiromi | Northcott, Paul A. | Pajic, Marina | Papaemmanuil, Elli | Paradiso, Angelo | Pearson, John V. | Puente, Xose S. | Raine, Keiran | Ramakrishna, Manasa | Richardson, Andrea L. | Richter, Julia | Rosenstiel, Philip | Schlesner, Matthias | Schumacher, Ton N. | Span, Paul N. | Teague, Jon W. | Totoki, Yasushi | Tutt, Andrew N.J. | Valdés-Mas, Rafael | van Buuren, Marit M. | van ’t Veer, Laura | Vincent-Salomon, Anne | Waddell, Nicola | Yates, Lucy R. | Zucman-Rossi, Jessica | Futreal, P. Andrew | McDermott, Ultan | Lichter, Peter | Meyerson, Matthew | Grimmond, Sean M. | Siebert, Reiner | Campo, Elías | Shibata, Tatsuhiro | Pfister, Stefan M. | Campbell, Peter J. | Stratton, Michael R.
Nature  2013;500(7463):415-421.
All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.
PMCID: PMC3776390  PMID: 23945592
8.  The Impact of Height during Childhood on the National Prevalence Rates of Overweight 
PLoS ONE  2014;9(1):e85769.
It is known that height and body mass index (BMI) are correlated in childhood. However, its impact on the (trend of) national prevalence rates of overweight and obesity has never been investigated. The aim of our study is to investigate the relation between height and national prevalence rates of overweight and obesity in childhood between 1980, 1997, and 2009, and to calculate which fixed value of p (2.0,2.1, …,3.0) in kg/mp during childhood is most accurate in predicting adult overweight.
Methods and findings
Cross-sectional growth data of children from three Dutch nationwide surveys in 1980, 1997, and 2009, and longitudinal data from the Terneuzen Birth Cohort and the Harpenden Growth Study were used. Relative risks (RR) and 95% confidence intervals (CI) were calculated. Our study showed that tall (>1 standard deviation (SD)) girls aged 5.0–13.9 y were more often overweight (RR = 3.5,95%CI:2.8–4.4) and obese (RR = 3.9,95%CI:2.1–7.4) than short girls (<−1 SD). Similar results were found in boys aged 5.0–14.9 y (RR = 4.4,95%CI:3.4–5.7 and RR = 5.3,95%CI:2.6–11.0). No large differences were found in the other age groups and in comparison with children with an average stature. Tall boys aged 2.0–4.9 y had a significantly higher positive trend in overweight between 1980 and 1997 compared to short boys (RR = 4.0,95%CI:1.38–11.9). For other age groups and in girls, no significant trends were found. The optimal Area Under the Curve (AUC) to predict adult overweight was found for p = 2.0.
Conclusions and significance
Tall girls aged 5.0–13.9y and tall boys aged 5.0–14.9y have much higher prevalence rates of overweight and obesity than their shorter peers. We suggest taking into account the impact of height when evaluating trends and variations of BMI distributions in childhood, and to use BMI to predict adult overweight.
PMCID: PMC3899068  PMID: 24465694
9.  Quality evaluation through self-assessment: a novel method to gain insight into ERCP performance 
Frontline Gastroenterology  2013;5(1):10-16.
The American Society for Gastrointestinal Endoscopy Committee on Outcomes Research has recommended monitoring nine endoscopic retrograde cholangiopancreatography (ERCP)-specific quality indicators for quality assurance in ERCP. With the development of a self-assessment tool for ERCP (Rotterdam Assessment Form for ERCP—RAF-E), key indicators can easily be assessed.
The aim of this study was to test in daily practice an easy-to-use form for assessment of procedural quality in ERCP and to determine ERCP quality outcomes in a tertiary referral hospital.
This was a prospective study carried out in a tertiary referral hospital. In January 2008, a quality self-assessment programme was started. Five qualified endoscopists participated in this study. All ERCPs were appraised using RAF-E. Primary parameters were common bile duct (CBD) cannulation rate and procedural success. The indication was classified and procedural difficulty was graded; success rates of therapeutic interventions were measured for all different difficulty degrees.
A total number of 1691 ERCPs were performed. 1515 (89.6%) of these were appraised using RAF-E. Median CBD cannulation success rate was 94.1%. Successful sphincterotomy was accomplished in almost all patients (median 100%; range 98.2–100%). Stent placement was successful in 97.8% and complete stone extraction, if indicated, was achieved in 86.8%.
Quality indicators for ERCP can be measured using the Rotterdam self-assessment programme for ERCP. Outcome data in ERCPs obtained with this RAF-E provide insight into the quality of individual as well as group performance and can be used to assess and set standards for quality control in ERCP.
PMCID: PMC3880906  PMID: 24416502
12.  Trends in birth weight and the prevalence of low birth weight and small-for-gestational-age in Surinamese South Asian babies since 1974: cross-sectional study of three birth cohorts 
BMC Public Health  2013;13:931.
South Asian babies born in developed countries are generally lighter than babies from other ethnic groups born in the same country. While the mean birth weight of Caucasian babies in the Netherlands has increased the past decades, it is unknown if the mean birth weight of South Asian babies born in the Netherlands has increased or if the prevalence of low birth weight (LBW) or small-for-gestational-age (SGA) has decreased.
The aims of this study are: 1. to investigate secular changes in mean birth weight and the prevalence of LBW and SGA in Surinamese South Asian babies, and 2. to assess differences between Surinamese South Asian and Dutch Caucasian neonates born 2006–2009.
A population based study for which neonatal characteristics of 2014 Surinamese South Asian babies, born between 1974 and 2009 in the Netherlands, and 3104 Dutch Caucasian babies born 2006–2009 were obtained from well-baby clinic records. LBW was defined as a birth weight <2500 g. SGA was based on a universal population standard (the Netherlands) and three ethnic specific standards (the Netherlands, UK, Canada).
In Surinamese South Asian babies from 1974 to 2009 no secular trend in mean birth weight and prevalence of LBW was found, whereas SGA prevalence decreased significantly.
Surinamese South Asian babies born in 2006–2009 (2993 g; 95% CI 2959-3029 g) were 450 g lighter than Dutch Caucasian babies (3448 g; 95% CI 3429-3468 g), while LBW and SGA prevalences, based on universal standards, were three times higher. Application of ethnic specific standards from the Netherlands and the UK yielded SGA rates in Surinamese South Asian babies that were similar to Dutch. There were considerable differences between the standards used.
Since 1974, although the mean birth weight of Surinamese South Asian babies remained unchanged, they gained a healthier weight for their gestational age.
PMCID: PMC3851477  PMID: 24098977
Birth weight; Infant, low birth weight; Infant, small for gestational age; India; The Netherlands
13.  Trends in Menarcheal Age between 1955 and 2009 in the Netherlands 
PLoS ONE  2013;8(4):e60056.
To assess and compare the secular trend in age at menarche in Dutch girls (1955–2009) and girls from Turkish and Moroccan descent living in the Netherlands (1997–2009).
Data on growth and maturation were collected in 20,867 children of Dutch, Turkish and Moroccan descent in 2009 by trained health care professionals. Girls, 9 years and older, of Dutch (n = 2138), Turkish (n = 282), and Moroccan (n = 295) descent were asked whether they had experienced their first period. We compared median menarcheal age in 2009 with data from the previous Dutch Nationwide Growth Studies in 1955, 1965, 1980 and 1997. Age specific body mass index (BMI) z-scores were calculated to assess differences in BMI between pre- and postmenarcheal girls in different age groups.
Median age at menarche in Dutch girls, decreased significantly from 13.66 years in 1955 to 13.15 years in 1997 and 13.05 years in 2009. Compared to Dutch girls there is a larger decrease in median age of menarche in girls of Turkish and Moroccan descent between 1997 and 2009. In Turkish girls age at menarche decreased from 12.80 to 12.50 years and in Moroccan girls from 12.90 to 12.60 years. Thirty-three percent of Turkish girls younger than 12 years start menstruating in primary school. BMI-SDS is significantly higher in postmenarcheal girls than in premenarcheal girls irrespective of age.
There is a continuing secular trend in earlier age at menarche in Dutch girls. An even faster decrease in age at menarche is observed in girls of Turkish and Moroccan descent in the Netherlands.
PMCID: PMC3620272  PMID: 23579990
14.  Marked Regression of Left Ventricular Hypertrophy after Outflow Desobliteration in HOCM 
Case Reports in Medicine  2012;2012:546942.
We present an HOCM patient in whom marked regression of left ventricular hypertrophy occurred within two years following outflow desobliteration by percutaneous septal ablation. Maximum wall thickness (initially documented by both echo and MRI) decreased from 34 mm to 22 mm (followup by echo only due to presence of the ICD), crossing the threshold value of 30 mm which was one of the risk markers that had triggered the primary prophylactic ICD implantation in this case prior to septal ablation.
PMCID: PMC3469106  PMID: 23082078
15.  TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients 
Oncoimmunology  2012;1(4):409-418.
There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.
PMCID: PMC3382882  PMID: 22754759
T-cell reactivity; TIL therapy; high throughput screening; pMHC multiplexing; tumor immunology
16.  Prevalence of Autoimmune Pancreatitis and Other Benign Disorders in Pancreatoduodenectomy for Presumed Malignancy of the Pancreatic Head 
Digestive Diseases and Sciences  2012;57(9):2458-2465.
Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided.
All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked.
A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients.
The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.
Electronic supplementary material
The online version of this article (doi:10.1007/s10620-012-2191-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3428528  PMID: 22588243
Autoimmune pancreatitis; Autoimmune cholangitis; IgG4; Pancreatoduodenectomy; IgG4 related systemic disease
17.  Pneumothorax Following ERCP: Report of Four Cases and Review of the Literature 
Digestive Diseases and Sciences  2012;57(8):1990-1995.
We report four patients with pneumothorax as a complication of ERCP with sphincterotomy. With conservative treatment all patients recovered. Previously, 16 comparable cases have been reported in the literature. The main risk factor for this rare complication seems (pre-cut) sphincterotomy. Pneumothorax is usually right-sided or bilateral and accompanied by pneumomediastinum, pneumoretroperitoneum and subcutaneous emphysema. The prognosis seems favourable with a non-surgical approach including intravenous antibiotics, fasting and when indicated chest tube drainage.
PMCID: PMC3405237  PMID: 22466080
ERCP; Sphincterotomy; Pneumothorax; Complication
18.  Low Resolution Limits and Inaccurate Algorithms Decrease Significantly the Value of Late Loss in Current Drug-Eluting Stent Trials 
Quantitative coronary and vascular angiography (QCA resp., QVA) remains the current gold standard for evaluation of restenosis. Late loss as one of the most commonly accepted parameters to highlight efficacy of the various devices has shown high correlation to clinical parameters but, surprisingly, has no impact on the evaluation of the remaining amount of restenostic tissue. The current clinical practice leads to unrealistic late loss calculations. Smaller late loss differences are usually not greater than the inherited resolution limits of QCA, which is especially the case in small differences between the various stents in the drug-eluting stent era. Late loss include additional systematic and random errors, due to the fact that measurements were taken at two different time points including the inherited resolution and calibration limits of QCA on two occasions. Due to the limited value of late loss in discriminating the small differences between the one and other DES, late lumen area loss and clearly defined calculation algorithms (e.g., MLD-relocation) should be used in future DES studies also to fulfill the more stringent regulatory requirements.
PMCID: PMC3317211  PMID: 22489271
19.  Lipid apheresis: oxidative stress, rheology, and vasodilatation 
In the treatment of homozygous and therapy-resistant hypercholesterolemia, lipid apheresis enables not only low density lipoprotein (LDL) cholesterol to be lowered by approximately 60%, but also oxidative stress factors to be influenced and adhesion molecules reduced. This was investigated in a group of 12 patients using the heparin-induced extracorporeal LDL precipitation (H.E.L.P.) procedure.
A significant lowering of LDL cholesterol and fibrinogen leads to an improvement in rheology and endothelial function, detectable and measurable within approximately 20 h by assessing minimum coronary resistance using positron emission tomography (PET) performed in 35 patients. This effect is detectable even after the first lipid apheresis session (H.E.L.P. procedure), documented in 12 patients.
Lipid apheresis appears to be the most effective procedure in the treatment of elevated lipoprotein(a) [Lp(a)]. A chosen group of nine patients with selective elevated Lp(a) illustrated both the influence on endothelial dysfunction, in the shape of sharply increased minimum coronary resistance, and the reduction through lipid apheresis, indicating that Lp(a) seems to exert a similar effect on the vascular wall and vascular function as LDL cholesterol.
PMCID: PMC3374116  PMID: 22528131
Lipid apheresis; Hypercholesterolemia; Lipoprotein(a)
20.  Healthy Growth in Children with Down Syndrome 
PLoS ONE  2012;7(2):e31079.
To provide cross-sectional height and head circumference (HC) references for healthy Dutch children with Down syndrome (DS), while considering the influence of concomitant disorders on their growth, and to compare growth between children with DS and children from the general population.
Study design
Longitudinal growth and medical data were retrospectively collected from medical records in 25 of the 30 regional hospital-based outpatient clinics for children with DS in the Netherlands. Children with Trisomy 21 karyotype of Dutch descent born after 1982 were included. The LMS method was applied to fit growth references.
We enrolled 1,596 children, and collected 10,558 measurements for height and 1,778 for HC. Children with DS without concomitant disorders (otherwise healthy children) and those suffering only from mild congenital heart defects showed similar growth patterns. The established growth charts, based on all measurements of these two groups, demonstrate the three age periods when height differences between children with and without DS increase: during pregnancy, during the first three years of life, and during puberty. This growth pattern results in a mean final height of 163.4 cm in boys and 151.8 cm in girls (−2.9 standard deviation (SD) and −3.0 SD on general Dutch charts, respectively). Mean HC (0 to 15 months) was 2 SD less than in the general Dutch population. The charts are available at
Height and HC references showed that growth retardation in otherwise healthy children with DS meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller HC than the general Dutch population shows. With these references, health care professionals can optimize their preventive care: monitoring growth of individual children with DS optimal, so that growth retarding comorbidities can be identified early, and focusing on the critical age periods to establish ways to optimize growth.
PMCID: PMC3281925  PMID: 22363551
21.  Increase in Prevalence of Overweight in Dutch Children and Adolescents: A Comparison of Nationwide Growth Studies in 1980, 1997 and 2009 
PLoS ONE  2011;6(11):e27608.
To assess the prevalence of overweight and obesity among Dutch children and adolescents, to examine the 30-years trend, and to create new body mass index reference charts.
Nationwide cross-sectional data collection by trained health care professionals.
Participants: 10,129 children of Dutch origin aged 0–21 years.
Main Outcome Measures
Overweight (including obesity) and obesity prevalences for Dutch children, defined by the cut-off values on body mass index references according to the International Obesity Task Force.
In 2009, 12.8% of the Dutch boys and 14.8% of the Dutch girls aged 2–21 years were overweight and 1.8% of the boys and 2.2% of the girls were classified as obese. This is a two to three fold higher prevalence in overweight and four to six fold increase in obesity since 1980. Since 1997, a substantial rise took place, especially in obesity, which increased 1.4 times in girls and doubled in boys. There was no increase in mean BMI SDS in the major cities since 1997.
Overweight and obesity prevalences in 2009 were substantially higher than in 1980 and 1997. However, the overweight prevalence stabilized in the major cities. This might be an indication that the rising trend in overweight in the Netherlands is starting to turn.
PMCID: PMC3216980  PMID: 22110687
22.  A Selectable and Excisable Marker System for the Rapid Creation of Recombinant Poxviruses 
PLoS ONE  2011;6(9):e24643.
Genetic manipulation of poxvirus genomes through attenuation, or insertion of therapeutic genes has led to a number of vector candidates for the treatment of a variety of human diseases. The development of recombinant poxviruses often involves the genomic insertion of a selectable marker for purification and selection purposes. The use of marker genes however inevitably results in a vector that contains unwanted genetic information of no therapeutic value.
Methodology/Principal Findings
Here we describe an improved strategy that allows for the creation of marker-free recombinant poxviruses of any species. The Selectable and Excisable Marker (SEM) system incorporates a unique fusion marker gene for the efficient selection of poxvirus recombinants and the Cre/loxP system to facilitate the subsequent removal of the marker. We have defined and characterized this new methodological tool by insertion of a foreign gene into vaccinia virus, with the subsequent removal of the selectable marker. We then analyzed the importance of loxP orientation during Cre recombination, and show that the SEM system can be used to introduce site-specific deletions or inversions into the viral genome. Finally, we demonstrate that the SEM strategy is amenable to other poxviruses, as demonstrated here with the creation of an ectromelia virus recombinant lacking the EVM002 gene.
The system described here thus provides a faster, simpler and more efficient means to create clinic-ready recombinant poxviruses for therapeutic gene therapy applications.
PMCID: PMC3169633  PMID: 21931792
23.  The Terneuzen Birth Cohort. Longer exclusive breastfeeding duration is associated with leaner body mass and a healthier diet in young adulthood 
BMC Pediatrics  2011;11:33.
Breastfeeding (BF) is protective against overweight and is associated with dietary behaviour. The aims of our study were to assess the relationship between exclusive BF duration and BMI, waist circumference (WC) and waist-hip ratio (WHR) at adulthood, and to study whether dietary behaviour could explain the relationship between BF duration and the proxies of fat mass.
In 2004-2005, 822 subjects from the Terneuzen Birth Cohort (n = 2,604), aged 18-28 years, filled in postal questionnaires including sociodemographic factors and aspects of dietary behaviour (dietary pattern, and consumption of fruit and vegetables, snacks, sweetened beverages and alcohol); 737 subjects also underwent anthropometric measurements of weight, height, and waist and hip circumference. The relationship between exclusive BF duration and dietary outcomes was investigated by logistic regression analysis. The relationships of BF duration with the anthropometric measures were investigated by linear regression analyses. All results were corrected for age, gender and possible confounders. Finally, regression analyses were performed to investigate if diet factors had a mediating effect on the relationship between BF duration and fat mass.
A significant inverse dose-response relationship of BF duration was found for BMI (β-0.13, SE 0.06), WC (β-0.39, SE 0.18) and WHR (β-0.003, SE 0.001), after correction for age, gender and confounders. The odds ratio (OR) of exclusive BF duration in months for a breakfast frequency of at least 5 times a week was 1.16 (95%CI 1.06-1.27), and for snack consumption of less than twice a week was 1.15 (95%CI 1.06-1.25). Both ORs were corrected for age, gender and confounders. For other dietary outcomes, the results point in the same direction, i.e. a positive relationship with BF duration, but these were not statistically significant. A mediating effect of the diet factors on the association between BF and anthropometric outcomes was not shown.
Exclusive BF duration had a significant inverse dose-response relationship with BMI, WC and WHR at young adulthood. BF duration was positively related to a healthier diet at adulthood, but this did not explain the protective effect of BF against body fat. Our results underline the recommendation of the WHO to exclusively breastfeed for 6 months or longer.
PMCID: PMC3112108  PMID: 21569265
24.  Intraoperative assessment of biliary anatomy for prevention of bile duct injury: a review of current and future patient safety interventions 
Surgical Endoscopy  2011;25(8):2449-2461.
Bile duct injury (BDI) is a dreaded complication of cholecystectomy, often caused by misinterpretation of biliary anatomy. To prevent BDI, techniques have been developed for intraoperative assessment of bile duct anatomy. This article reviews the evidence for the different techniques and discusses their strengths and weaknesses in terms of efficacy, ease, and cost-effectiveness.
PubMed was searched from January 1980 through December 2009 for articles concerning bile duct visualization techniques for prevention of BDI during laparoscopic cholecystectomy.
Nine techniques were identified. The critical-view-of-safety approach, indirectly establishing biliary anatomy, is accepted by most guidelines and commentaries as the surgical technique of choice to minimize BDI risk. Intraoperative cholangiography is associated with lower BDI risk (OR 0.67, CI 0.61–0.75). However, it incurs extra costs, prolongs the operative procedure, and may be experienced as cumbersome. An established reliable alternative is laparoscopic ultrasound, but its longer learning curve limits widespread implementation. Easier to perform are cholecystocholangiography and dye cholangiography, but these yield poor-quality images. Light cholangiography, requiring retrograde insertion of an optical fiber into the common bile duct, is too unwieldy for routine use. Experimental techniques are passive infrared cholangiography, hyperspectral cholangiography, and near-infrared fluorescence cholangiography. The latter two are performed noninvasively and provide real-time images. Quantitative data in patients are necessary to further evaluate these techniques.
The critical-view-of-safety approach should be used during laparoscopic cholecystectomy. Intraoperative cholangiography or laparoscopic ultrasound is recommended to be performed routinely. Hyperspectral cholangiography and near-infrared fluorescence cholangiography are promising novel techniques to prevent BDI and thus increase patient safety.
PMCID: PMC3142332  PMID: 21487883
Cholecystectomy; CBD; Common bile duct; Complications
25.  A randomised comparison of cognitive behavioural therapy (CBT) and eye movement desensitisation and reprocessing (EMDR) in disaster-exposed children 
European Journal of Psychotraumatology  2011;2:10.3402/ejpt.v2i0.5694.
Building on previous research with disaster-exposed children and adolescents, a randomised clinical trial was performed in the treatment of trauma-related symptoms. In the current study two active treatments were compared among children in a broad age range and from a wide diversity of ethnic populations.
The primary aim was to compare the effectiveness and efficiency of Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitisation and Reprocessing (EMDR).
Children (n=52, aged 4–18) were randomly allocated to either CBT (n=26) or EMDR (n=26) in a disaster mental health after-care setting after an explosion of a fireworks factory. All children received up to four individual treatment sessions over a 4–8 week period along with up to four sessions of parent guidance. Blind assessment took place pre- and post-treatment and at 3 months follow-up on a variety of parent-rated and self-report measures of post-traumatic stress disorder symptomatology, depression, anxiety, and behaviour problems. Analyses of variance (general linear model repeated measures) were conducted on the intention-to-treat sample and the completers.
Both treatment approaches produced significant reductions on all measures and results were maintained at follow-up. Treatment gains of EMDR were reached in fewer sessions.
Standardised CBT and EMDR interventions can significantly improve functioning of disaster-exposed children.
PMCID: PMC3402133  PMID: 22893815
Randomised controlled trial; eye movement desensitisation and reprocessing (EMDR); cognitive behavioural therapy (CBT); post-traumatic stress disorder (PTSD); disaster

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