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1.  The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes 
European Journal of Human Genetics  2010;18(9):999-1005.
Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.
PMCID: PMC2987413  PMID: 20531442
Holoprosencephaly; SHH; SIX3; ZIC2; TGIF; genotype–phenotype
2.  Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. 
Journal of Medical Genetics  1992;29(12):853-857.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.
PMCID: PMC1016200  PMID: 1362220
3.  Effects of task-oriented robot training on arm function, activity, and quality of life in chronic stroke patients: a randomized controlled trial 
Over fifty percent of stroke patients experience chronic arm hand performance problems, compromising independence in daily life activities and quality of life. Task-oriented training may improve arm hand performance after stroke, whereby augmented therapy may lead to a better treatment outcome. Technology-supported training holds opportunities for increasing training intensity. However, the effects of robot-supported task-oriented training with real life objects in stroke patients are not known to date. The aim of the present study was to investigate the effectiveness and added value of the Haptic Master robot combined with task-oriented arm hand training in chronic stroke patients.
In a single-blind randomized controlled trial, 22 chronic stroke patients were randomly allocated to receive either task-oriented robot-assisted arm-hand training (experimental group) or task-oriented non-robotic arm-hand training (control group). For training, the T-TOAT (Technology-supported Task-Oriented Arm Training) method was applied. Training was provided during 8 weeks, 4 times/week, 2× 30 min/day.
A significant improvement after training on the Action Research Arm Test (ARAT) was demonstrated in the experimental group (p = 0.008). Results were maintained until 6 months after cessation of the training. On the perceived performance measure (Motor Activity Log (MAL)), both, the experimental and control group improved significantly after training (control group p = 0.008; experimental group p = 0.013). The improvements on MAL in both groups were maintained until 6 months after cessation of the training. With regard to quality of life, only in the control group a significant improvement after training was found (EuroQol-5D p = 0.015, SF-36 physical p = 0.01). However, the improvement on SF-36 in the control group was not maintained (p = 0.012). No between-group differences could be demonstrated on any of the outcome measures.
Arm hand performance improved in chronic stroke patients, after eight weeks of task oriented training. The use of a Haptic Master robot in support of task-oriented arm training did not show additional value over the video-instructed task-oriented exercises in highly functional stroke patients.
Clinical trial registration information
Current Controlled Trials ISRCTN82787126
PMCID: PMC3973831  PMID: 24684808
Stroke; Hemiplegia; Robotics; Computer-assisted therapy; Rehabilitation; Upper extremity; Arm; Hand; Motor skills; Automation
4.  Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration 
The Journal of pathology  2013;229(5):645-659.
Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent ‘normal’ proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive – indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo – arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration.
PMCID: PMC3951144  PMID: 23124355
proximal tubules; progenitor cell; regeneration; acute tubular necrosis
5.  The Sum of Its Parts—Effects of Gastric Distention, Nutrient Content and Sensory Stimulation on Brain Activation 
PLoS ONE  2014;9(3):e90872.
During food consumption the brain integrates multiple interrelated neural and hormonal signals involved in the regulation of food intake. Factors influencing the decision to stop eating include the foods' sensory properties, macronutrient content, and volume, which in turn affect gastric distention and appetite hormone responses. So far, the contributions of gastric distention and oral stimulation by food on brain activation have not been studied. The primary objective of this study was to assess the effect of gastric distention with an intra-gastric load and the additional effect of oral stimulation on brain activity after food administration. Our secondary objective was to study the correlations between hormone responses and appetite-related ratings and brain activation. Fourteen men completed three functional magnetic resonance imaging sessions during which they either received a naso-gastric infusion of water (stomach distention), naso-gastric infusion of chocolate milk (stomach distention + nutrients), or ingested chocolate-milk (stomach distention + nutrients + oral exposure). Appetite ratings and blood parameters were measured at several time points. During gastric infusion, brain activation was observed in the midbrain, amygdala, hypothalamus, and hippocampus for both chocolate milk and water, i.e., irrespective of nutrient content. The thalamus, amygdala, putamen and precuneus were activated more after ingestion than after gastric infusion of chocolate milk, whereas infusion evoked greater activation in the hippocampus and anterior cingulate. Moreover, areas involved in gustation and reward were activated more after oral stimulation. Only insulin responses following naso-gastric infusion of chocolate milk correlated with brain activation, namely in the putamen and insula. In conclusion, we show that normal (oral) food ingestion evokes greater activation than gastric infusion in stomach distention and food intake-related brain areas. This provides neural evidence for the importance of sensory stimulation in the process of satiation.
Trial Registration NCT01644539.
PMCID: PMC3948722  PMID: 24614074
6.  Smelly primes – when olfactory primes do or do not work 
In applied olfactory cognition the effects that olfactory stimulation can have on (human) behavior are investigated. To enable an efficient application of olfactory stimuli a model of how they may lead to a change in behavior is proposed. To this end we use the concept of olfactory priming. Olfactory priming may prompt a special view on priming as the olfactory sense has some unique properties which make odors special types of primes. Examples of such properties are the ability of odors to influence our behavior outside of awareness, to lead to strong affective evaluations, to evoke specific memories, and to associate easily and quickly to other environmental stimuli. Opportunities and limitations for using odors as primes are related to these properties, and alternative explanations for reported findings are offered. Implications for olfactory semantic, construal, behavior and goal priming are given based on a brief overview of the priming literature from social psychology and from olfactory perception science. We end by formulating recommendations and ideas for a future research agenda and applications for olfactory priming.
PMCID: PMC3921890  PMID: 24575071
olfaction; priming; cognition and emotion; behavior; valence
7.  Why clinicians do not implement integrated treatment for comorbid substance use disorder and posttraumatic stress disorder: a qualitative study 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.22821.
Healthcare providers working in addiction facilities do not often implement integrated treatment of comorbid substance use disorder (SUD) and posttraumatic stress disorder (PTSD) while there is empirical evidence to do so.
This study aims to get insight into the views of clinicians with regard to the diagnosis and treatment of PTSD in SUD patients.
A qualitative research method was chosen. Fourteen treatment staff members of different wards of an addiction care facility were interviewed by an independent interviewer.
Despite acknowledging adverse consequences of trauma exposure on SUD, severe underdiagnosis of PTSD was mentioned and treatment of PTSD during SUD treatment was not supported. Obstacles related to the underestimation of PTSD among SUD patients and to the perceptions of SUD clinicians concerning the treatment of comorbid SUD/PTSD were reported.
It is concluded that SUD facilities should train their clinicians to enable them to provide for integrated treatment of SUD/PTSD.
PMCID: PMC3916674  PMID: 24511368
Addiction; trauma; qualitative; healthcare provider; perceptions
8.  Updating the profile of C-terminal MECP2 deletions in Rett syndrome 
Journal of medical genetics  2009;47(4):242-248.
This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions.
Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared.
Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region.
In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome.
PMCID: PMC3913726  PMID: 19914908
9.  Schmallenberg Virus Circulation in Culicoides in Belgium in 2012: Field Validation of a Real Time RT-PCR Approach to Assess Virus Replication and Dissemination in Midges 
PLoS ONE  2014;9(1):e87005.
Indigenous Culicoides biting midges are suggested to be putative vectors for the recently emerged Schmallenberg virus (SBV) based on SBV RNA detection in field-caught midges. Furthermore, SBV replication and dissemination has been evidenced in C. sonorensis under laboratory conditions. After SBV had been detected in Culicoides biting midges from Belgium in August 2011, it spread all over the country by the end of 2011, as evidenced by very high between-herd seroprevalence rates in sheep and cattle. This study investigated if a renewed SBV circulation in midges occurred in 2012 in the context of high seroprevalence in the animal host population and evaluated if a recently proposed realtime RT-PCR approach that is meant to allow assessing the vector competence of Culicoides for SBV and bluetongue virus under laboratory conditions was applicable to field-caught midges. Therefore midges caught with 12 OVI traps in four different regions in Belgium between May and November 2012, were morphologically identified, age graded, pooled and tested for the presence of SBV RNA by realtime RT-PCR. The results demonstrate that although no SBV could be detected in nulliparous midges caught in May 2012, a renewed but short lived circulation of SBV in parous midges belonging to the subgenus Avaritia occured in August 2012 at all four regions. The infection prevalence reached up to 2.86% in the south of Belgium, the region where a lower seroprevalence was found at the end of 2011 than in the rest of the country. Furthermore, a frequency analysis of the Ct values obtained for 31 SBV-S segment positive pools of Avaritia midges showed a clear bimodal distribution with peaks of Ct values between 21–24 and 33–36. This closely resembles the laboratory results obtained for SBV infection of C. sonorensis and implicates indigenous midges belonging to the subgenus Avaritia as competent vectors for SBV.
PMCID: PMC3900700  PMID: 24466312
10.  Best diagnostic approach for the genetic evaluation of fetuses after intrauterine death in first, second or third trimester: QF-PCR, karyotyping and/or genome wide SNP array analysis 
The aim of this study was to evaluate the best diagnostic approach for the genetic analysis of samples from first, second and third trimester intrauterine fetal deaths (IUFDs). We examined a total of 417 IUFD samples from fetuses with and without congenital anomalies. On 414 samples, karyotyping (N = 46) and/or rapid aneuploidy testing by QF-PCR (N = 371) was performed). One hundred sixty eight samples with a normal test result were subsequently tested by genome wide Single Nucleotide Polymorphism (SNP) array analysis. Three samples were only analyzed by array.
In 50 (12.0%) samples an aneuploidy was detected by QF-PCR and/or karyotyping, representing 47.1% of first, 13.2% of second and 3.4% of third trimester pregnancies. Karyotyping and QF-PCR failed in 4 (8.7%) and 7 (1.9%) samples, respectively, concerning mostly contaminated amniotic fluid samples from third trimester pregnancies.
Clinically relevant aberrations were identified in 4.2% (all fetuses with malformations) of the 168 samples tested by SNP array. Inherited copy number variants (CNVs) were detected in 5.4% and 8.9% showed CNVs of unknown clinical relevance as parental inheritance could not be studied yet. In a sample from a fetus suspect for Meckel-Grüber syndrome, the genotype information from the SNP array revealed various stretches of homozygosity, including one stretch encompassing the CEP290 gene. Subsequent CEP290 mutation analysis revealed a homozygous, pathogenic mutation in this gene.
Based on our experience we recommend QF-PCR as the first-line test in IUFD samples of first and second trimester pregnancies to exclude aneuploidy before performing array analysis. The chance to detect aneuploidy in third trimester pregnancies is relatively low and therefore array analysis can be performed as a first-tier test. A tissue sample, instead of amniotic fluid, is preferred because of a higher success rate in testing.
We emphasize the need for analysis of parental samples whenever a rare, unique CNV is detected to allow for better interpretation of such findings and to improve future pregnancy management. Furthermore, we illustrate the strength of SNP arrays for genotype analysis, even though we realize it is crucial to have detailed phenotypic information to make optimal use of the genotype data in finding candidate recessive genes that may be related to the fetal phenotype.
PMCID: PMC3906897  PMID: 24428858
Intrauterine fetal death; IUFD; DNA; QF-PCR; Karyotyping; SNP array
11.  Psychiatric comorbidity among terminally ill patients in general practice in the Netherlands: a comparison between patients with cancer and heart failure 
It is unclear whether psychiatric disorders are specifically related to the terminal phase of cancer, or independent of the underlying disease.
To investigate the rate of psychiatric comorbidity and psychotropic drugs prescription in terminally ill patients in the GP setting, comparing both patients with terminal cancer and heart failure.
Design and setting
Retrospective cohort study using the Utrecht General Practitioner Research Network.
Equally-sized groups of patients with terminal cancer and heart failure were randomly selected from the database of four general practices over the years 2005–2009. Psychiatric comorbidities were determined using the International Classification for Primary Care (ICPC) codes and psychotropic drugs prescriptions using the Anatomical Therapeutic Chemical (ATC) Classification System codes.
A total of 191 terminally ill patients were included in the study (111 with cancer and 80 with heart failure). The mean age for patients with terminal cancer (70.8 years, standard deviation [SD] = 12.8) was 15 years younger than that of patients with heart failure (85.6 years, SD = 9.2). Half of the terminally ill patients (50.3 %) were prescribed psychotropics, but only 13.6% of them had obtained a psychiatric diagnosis. There were no significant differences in prevalence of psychiatric disease and psychotropic drug prescription between patients with terminal cancer and heart failure.
The results demonstrate a high use of psychotropic drugs in terminally ill patients, often in the absence of a formal diagnosis of a psychiatric disorder. The absence of differences between patients with cancer and heart failure suggests that psychiatric diagnoses and increased psychotropic prescriptions are primarily related to the terminal stage of the disease and not to the background of cancer or heart failure.
PMCID: PMC3529294  PMID: 23336475
cancer; heart failure; general practitioners; psychiatry; psychotropic; drugs; terminal care
12.  The effects of odor and body posture on perceived duration 
This study reports an examination of the internal clock model, according to which subjective time duration is influenced by attention and arousal state. In a time production task, we examine the hypothesis that an arousing odor and an upright body posture affect perceived duration. The experimental task was performed while participants were exposed to an odor and either sitting upright (arousing condition) or lying down in a relaxing chair (relaxing condition). They were allocated to one of three experimental odor conditions: rosemary (arousing condition), peppermint (relaxing condition), and no odor (control condition). The predicted effects of the odors were not borne out by the results. Self-reported arousal (SRA) and pleasure (PL) states were measured before, during (after each body posture condition) and postexperimentally. Heart rate (HR) and skin conductance were measured before and during the experiment. As expected, odor had an effect on perceived duration. When participants were exposed to rosemary odor, they produced significantly shorter time intervals than in the no odor condition. This effect, however, could not be explained by increased arousal. There was no effect of body posture on perceived duration, even though body posture did induce arousal. The results do not support the proposed arousal mechanism of the internal clock model.
PMCID: PMC3915145  PMID: 24567718
perceived duration; internal clock; arousal; affective state; body posture; odor
13.  Danger Signals in the Initiation of the Inflammatory Response after Myocardial Infarction 
Mediators of Inflammation  2013;2013:206039.
During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.
PMCID: PMC3864081  PMID: 24363498
14.  Effect of Replacing Sugar with Non-Caloric Sweeteners in Beverages on the Reward Value after Repeated Exposure 
PLoS ONE  2013;8(11):e81924.
The reward value of food is partly dependent on learned associations. It is not yet known whether replacing sugar with non-caloric sweeteners in food is affecting long-term acceptance.
To determine the effect of replacing sugar with non-caloric sweeteners in a nutrient-empty drink (soft drink) versus nutrient-rich drink (yoghurt drink) on reward value after repeated exposure.
We used a randomized crossover design whereby forty subjects (15 men, 25 women) with a mean±SD age of 21±2 y and BMI of 21.5±1.7 kg/m2 consumed a fixed portion of a non-caloric sweetened (NS) and sugar sweetened (SS) versions of either a soft drink or a yoghurt drink (counterbalanced) for breakfast which were distinguishable by means of colored labels. Each version of a drink was offered 10 times in semi-random order. Before and after conditioning the reward value of the drinks was assessed using behavioral tasks on wanting, liking, and expected satiety. In a subgroup (n=18) fMRI was performed to assess brain reward responses to the drinks.
Outcomes of both the behavioral tasks and fMRI showed that conditioning did not affect the reward value of the NS and SS versions of the drinks significantly. Overall, subjects preferred the yoghurt drinks to the soft drinks and the ss drinks to the NS drinks. In addition, they expected the yoghurt drinks to be more satiating, they reduced hunger more, and delayed the first eating episode more. Conditioning did not influence these effects.
Our study showed that repeated consumption of a non-caloric sweetened beverage, instead of a sugar sweetened version, appears not to result in changes in the reward value. It cannot be ruled out that learned associations between sensory attributes and food satiating capacity which developed preceding the conditioning period, during lifetime, affected the reward value of the drinks.
PMCID: PMC3842969  PMID: 24312382
15.  Measures and procedures utilized to determine the added value of microprocessor-controlled prosthetic knee joints: a systematic review 
The effectiveness of microprocessor-controlled prosthetic knee joints (MPKs) has been assessed using a variety of outcome measures in a variety of health and health-related domains. However, if the patient is to receive a prosthetic knee joint that enables him to function optimally in daily life, it is vital that the clinician has adequate information about the effects of that particular component on all aspects of persons’ functioning. Especially information concerning activities and participation is of high importance, as this component of functioning closely describes the person’s ability to function with the prosthesis in daily life. The present study aimed to review the outcome measures that have been utilized to assess the effects of microprocessor-controlled prosthetic knee joints (MPK), in comparison with mechanically controlled prosthetic knee joints, and aimed to classify these measures according to the components and categories of functioning defined by the International Classification of Functioning, Disability and Health (ICF). Subsequently, the gaps in the scientific evidence regarding the effectiveness of MPKs were determined.
A systematic literature search in 6 databases (i.e. PubMed, CINAHL, Cochrane Library, Embase, Medline and PsychInfo) identified scientific studies that compared the effects of using MPKs with mechanically controlled prosthetic knee joints on persons’ functioning. The outcome measures that have been utilized in those studies were extracted and categorized according to the ICF framework. Also, a descriptive analysis regarding all studies has been performed.
A total of 37 studies and 72 outcome measures have been identified. The majority (67%) of the outcome measures that described the effects of using an MPK on persons’ actual performance with the prosthesis covered the ICF body functions component. Only 31% of the measures on persons’ actual performance investigated how an MPK may affect performance in daily life. Research also typically focused on young, fit and active persons.
Scientifically valid evidence regarding the performance of persons with an MPK in everyday life is limited. Future research should specifically focus on activities and participation to increase the understanding of the possible functional added value of MPKs.
PMCID: PMC3890588  PMID: 24279314
Rehabilitation; Functioning; Review; Classification; Amputation; Lower extremities; Microprocessor-controlled knee joint
16.  PROPER I: frequency and appropriateness of psychotropic drugs use in nursing home patients and its associations: a study protocol 
BMC Psychiatry  2013;13:307.
Nursing home patients with dementia use psychotropic drugs longer and more frequently than recommended by guidelines implying psychotropic drugs are not always prescribed appropriately. These drugs can have many side effects and effectiveness is limited. Psychotropic drug use between nursing home units varies and is not solely related to the severity of neuropsychiatric symptoms. There is growing evidence indicating that psychotropic drug use is associated with environmental factors, suggesting that the prescription of psychotropic drugs is not only related to (objective) patient factors. However, other factors related to the patient, elderly care physician, nurse and the physical environment are only partially identified. Using a mixed method of qualitative and quantitative research, this study aims to understand the nature of psychotropic drug use and its underlying factors by identifying: 1) frequency and appropriateness of psychotropic drug use for neuropsychiatric symptoms in nursing home patients with dementia, 2) factors associated with (appropriateness of) psychotropic drug use.
A cross-sectional mixed methods study. For the quantitative study, patients with dementia (n = 540), nursing staff and elderly care physicians of 36 Dementia Special Care Units of 12 nursing homes throughout the Netherlands will be recruited. Six nursing homes with high average rates and six with low average rates of psychotropic drug use, based on a national survey about frequency of psychotropic drug use on units, will be included. Psychotropic drugs include antipsychotics, anxiolytics, hypnotics, antidepressants, anticonvulsants and anti-dementia drugs. Appropriateness will be measured by an instrument based on the Medication Appropriateness Index and current guidelines for treatment of neuropsychiatric symptoms. Factors associated to psychotropic drug use, related to the patient, elderly care physician, nurse and physical environment, will be explored using multilevel regression analyses. For the qualitative study, in depth interviews with staff will be held and analyzed to identify and explore other unknown factors.
This study will provide insight into factors that are associated with the frequency and appropriateness of psychotropic drug use for neuropsychiatric symptoms. Understanding psychotropic drug use and its associations may contribute to better dementia care.
PMCID: PMC3840691  PMID: 24238392
Nursing home; Dementia; Neuropsychiatric symptoms; Psychotropic drug use; Environment
17.  Improving psychotropic drug prescription in nursing home patients with dementia: design of a cluster randomized controlled trial 
BMC Psychiatry  2013;13:280.
Neuropsychiatric symptoms are highly prevalent in nursing home patients with dementia. Despite modest effectiveness and considerable side effects, psychotropic drugs are frequently prescribed for these neuropsychiatric symptoms. This raises questions whether psychotropic drugs are appropriately prescribed. The aim of the PROPER (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia) II study is to investigate the efficacy of an intervention for improving the appropriateness of psychotropic drug prescription in nursing home patients with dementia.
The PROPER II study is a multi-center cluster randomized controlled, pragmatic trial using parallel groups. It has a duration of eighteen months and four six-monthly assessments. Six nursing homes will participate in the intervention and six will continue care as usual. The nursing homes will be located throughout the Netherlands, each participating with two dementia special care units with an average of fifteen patients per unit, resulting in 360 patients. The intervention consists of a structured and repeated multidisciplinary medication review supported by education and continuous evaluation. It is conducted by pharmacists, physicians, and nurses and consists of three components: 1) preparation and education, 2) conduct, and 3) evaluation/guidance. The primary outcome is the proportion of patients with appropriate psychotropic drug use. Secondary outcomes are the overall frequency of psychotropic drug use, neuropsychiatric symptoms, quality of life, activities of daily living, psychotropic drug side effects and adverse events (including cognition, comorbidity, and mortality). Besides, a process analysis on the intervention will be carried out.
This study is expected to improve the appropriateness of psychotropic drug prescription for neuropsychiatric symptoms in nursing home patients with dementia by introducing a structured and repeated multidisciplinary medication review supported by education and continuous evaluation.
Trial registration
Netherlands Trial Registry (NTR): NTR3569.
PMCID: PMC3840636  PMID: 24180295
Dementia; Psychotropic drugs; Nursing homes; Medication safety; Clinical trial
18.  Observational skills assessment score: reliability in measuring amount and quality of use of the affected hand in unilateral cerebral palsy 
BMC Neurology  2013;13:152.
The Observational Skills Assessment Score (OSAS) measures amount and quality of use of the affected hand in children with unilateral Cerebral Palsy (CP) in bimanual activities and could therefore be a valuable addition to existing assessment tools. The OSAS consists of tasks that are age appropriate and require use of the affected hand.
To measure the agreement and reliability of the OSAS a convenience sample of two groups of 16 children with unilateral spastic CP (2.5-6 and 12–16 years old), performed age specific bimanual tasks in 2 measurement sessions. Three experienced raters took part in testing and 8 in scoring. Intra class correlation (ICC) values for intra- and inter-rater reliability, and the mean and standard deviation of the differences between measurements were calculated. For test-retest reliability beside ICC scores, Smallest Detectable Differences (SDDs) were calculated in 16 older and 10 younger children.
Generally, there seems to be good agreement between repeated measurements of the OSAS, as indicated by the small SDDs on most scales for quality of movement, compared to the range of their scales. This indicates potentially good sensitivity to change if used for patient evaluation purposes. The exceptions were the ‘quality of reach’ score for all tasks, and all quality scores for the stacking blocks task for the young children. As used in the present study, the OSAS has good discriminative capacity within patient populations as indicated by the high ICCs for most quality scores. Measuring the amount of use does not seem to be useful for either discrimination or evaluation.
In general, the OSAS seems to be a reliable tool for assessing the quality of use of the affected hand in bimanual activities in younger and older children with unilateral CP. Some modifications may improve its usefulness and efficiency.
PMCID: PMC3853931  PMID: 24139170
Cerebral palsy; Upper limb; Bimanual performance; Outcome assessment; Reliability
19.  Analysis of Initial Cell Spreading Using Mechanistic Contact Formulations for a Deformable Cell Model 
PLoS Computational Biology  2013;9(10):e1003267.
Adhesion governs to a large extent the mechanical interaction between a cell and its microenvironment. As initial cell spreading is purely adhesion driven, understanding this phenomenon leads to profound insight in both cell adhesion and cell-substrate interaction. It has been found that across a wide variety of cell types, initial spreading behavior universally follows the same power laws. The simplest cell type providing this scaling of the radius of the spreading area with time are modified red blood cells (RBCs), whose elastic responses are well characterized. Using a mechanistic description of the contact interaction between a cell and its substrate in combination with a deformable RBC model, we are now able to investigate in detail the mechanisms behind this universal power law. The presented model suggests that the initial slope of the spreading curve with time results from a purely geometrical effect facilitated mainly by dissipation upon contact. Later on, the spreading rate decreases due to increasing tension and dissipation in the cell's cortex as the cell spreads more and more. To reproduce this observed initial spreading, no irreversible deformations are required. Since the model created in this effort is extensible to more complex cell types and can cope with arbitrarily shaped, smooth mechanical microenvironments of the cells, it can be useful for a wide range of investigations where forces at the cell boundary play a decisive role.
Author Summary
How cells spread on a newly encountered surface is an important issue, since it hints at how cells interact physically with the specific material in general. It has been shown before that many cell types have very similar early spreading behavior. This observation has been linked to the mechanical nature of the phenomenon, during which a cell cannot yet react by changing its structure and behavior. Understanding in detail how this passive spreading occurs, and what clues a cell may later respond to is the goal of this work. At the same time, the model we develop here should be very valuable for more complex situations of interacting cells, since it is able to reproduce the purely mechanical response in detail. We find that spreading is limited mainly by energy dissipation upon contact and later dissipation in the cell's cortex and that no irreversible deformation occurs during the spreading of red blood cells on an adhesive surface.
PMCID: PMC3798278  PMID: 24146605
20.  TGF-beta1 Does Not Induce Senescence of Multipotent Mesenchymal Stromal Cells and Has Similar Effects in Early and Late Passages 
PLoS ONE  2013;8(10):e77656.
Transforming growth factor-beta 1 (TGF-β1) stimulates a broad range of effects which are cell type dependent, and it has been suggested to induce cellular senescence. On the other hand, long-term culture of multipotent mesenchymal stromal cells (MSCs) has a major impact on their cellular physiology and therefore it is well conceivable that the molecular events triggered by TGF-β1 differ considerably in cells of early and late passages. In this study, we analyzed the effect of TGF-β1 on and during replicative senescence of MSCs. Stimulation with TGF-β1 enhanced proliferation, induced a network like growth pattern and impaired adipogenic and osteogenic differentiation. TGF-β1 did not induce premature senescence. However, due to increased proliferation rates the cells reached replicative senescence earlier than untreated controls. This was also evident, when we analyzed senescence-associated DNA-methylation changes. Gene expression profiles of MSCs differed considerably at relatively early (P 3 - 5) and later passages (P 10). Nonetheless, relative gene expression differences provoked by TGF-β1 at individual time points or in a time course dependent manner (stimulation for 0, 1, 4 and 12 h) were very similar in MSCs of early and late passage. These results support the notion that TGF-β1 has major impact on MSC function, but it does not induce senescence and has similar molecular effects during culture expansion.
PMCID: PMC3798389  PMID: 24147049
21.  Extraction bradycardia: a pilot case-crossover study 
Head & Face Medicine  2013;9:29.
Significant vasovagal reaction is one of the untoward events in the course of simple extractions. The present study then aimed to record the patients’ heart rate during the extraction procedure.
Materials and methods
Informed consents were obtained in advance. Patients were placed in the dental chair and their heart rate was measured before /and prior to the anesthetic injection, during, and after dental extraction on a pulse oxymeter device. Data were analyzed using paired t-test.
Sixty one patients were included. The mean heart rates of these patients prior, during, and after extraction were 88, 86 and 81, respectively. Two by two comparisons showed a significant decrease in the mean heart rate during extraction compared to the baseline and also after extraction compared to both before and during extraction (p < 0.05 for all three).
Despite the presence of sufficient local anesthesia and performing the extraction with the least trauma, a significant decrease in heart rate is evident.
PMCID: PMC3854007  PMID: 24456612
Tooth extraction; Trigeminocardiac reflex; Bradycardia; Heart rate
22.  9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium 
Warren, Helen | Dudbridge, Frank | Fletcher, Olivia | Orr, Nick | Johnson, Nichola | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Mahmoodi, Maryam | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linda M. | Muir, Kenneth R. | Lophatananon, Artitaya | Chaiwerawattana, Arkom | Wiangnon, Surapon | Fasching, Peter A. | Beckmann, Matthias W. | Ekici, Arif B. | Schulz-Wendtland, Ruediger | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Bojesen, Stig E | Nielsen, Sune F. | Flyger, Henrik | Nordestgaard, Børge G | Milne, Roger L. | Benítez, Javier | Arias-Pérez, José-Ignacio | Zamora, M. Pilar | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Langheinz, Anne | Meindl, Alfons | Golatta, Michael | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Yuriy | Bermisheva, Marina | Prokofyeva, Darya | Zinnatullina, Guzel | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Hartikainen, Jaana M. | Kataja, Vesa | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Lambrechts, Diether | Smeets, Ann | Paridaens, Robert | Weltens, Caroline | Flesch-Janys, Dieter | Buck, Katharina | Behrens, Sabine | Peterlongo, Paolo | Bernard, Loris | Manoukian, Siranoush | Radice, Paolo | Couch, Fergus J. | Vachon, Celine | Wang, Xianshu | Olson, Janet | Giles, Graham | Baglietto, Laura | McLean, Cariona A. | Severi, Gianluca | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Mulligan, Anna Marie | Weerasooriya, Nayana | Devilee, Peter | Tollenaar, Robert A.E.M. | Martens, John W.M. | Seynaeve, Caroline M. | Hooning, Maartje J. | Hollestelle, Antoinette | Jager, Agnes | Tilanus-Linthorst, Madeleine M.A. | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Cox, Angela | Cross, Simon S. | Brock, Ian W. | Reed, Malcolm W.R. | Pharoah, Paul | Blows, Fiona M. | Dunning, Alison M. | Ghoussaini, Maya | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk | Easton, Douglas F. | Humphreys, Manjeet | Wang, Qin | Peto, Julian | dos-Santos-Silva, Isabel
Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).
To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).
This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10–29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10–143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10–22) but less strongly, if at all, with ER-negative (ER–) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10–6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors.
This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer.
The findings further support the view that genetic susceptibility varies according to tumor subtype.
PMCID: PMC3772723  PMID: 22859399
23.  Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer 
SpringerPlus  2013;2:480.
The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases.
Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases.
We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models.
Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated.
According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.
PMCID: PMC3786086  PMID: 24083118
Tumor chronology; Tumor biology; Lymph node; Metastasis; Breast cancer
24.  Morbidity and doctor characteristics only partly explain the substantial healthcare expenditures of frequent attenders: a record linkage study between patient data and reimbursements data 
BMC Family Practice  2013;14:138.
Frequently attending patients to primary care (FA) are likely to cost more in primary care than their non-frequently attending counterparts. But how much is spent on specialist care of FAs? We describe the healthcare expenditures of frequently attending patients during 1, 2 or 3 years and test the hypothesis that additional costs can be explained by FAs’ combined morbidity and primary care physicians’ characteristics.
Record linkage study. Pseudonymised clinical data from the medical records of 16 531 patients from 39 general practices were linked to healthcare insurer’s reimbursements data. Main outcome measures were all reimbursed primary and specialist healthcare costs between 2007 and 2009. Multilevel linear regression analysis was used to quantify the effects of the different durations of frequent attendance on three-year total healthcare expenditures in primary and specialist care, while adjusting for age, sex, morbidities and for primary care physicians characteristics. Primary care physicians’ characteristics were collected through administrative data and a questionnaire.
Unadjusted mean 3-year expenditures were 5044 and 15 824 Euros for non-FAs and three-year-FAs, respectively. After adjustment for all other included confounders, costs both in primary and specialist care remained substantially higher and increased with longer duration of frequent attendance. As compared to non-FAs, adjusted mean expenditures were 1723 and 5293 Euros higher for one-year and three-year FAs, respectively.
FAs of primary care give rise to substantial costs not only in primary, but also in specialist care that cannot be explained by their multimorbidity. Primary care physicians’ working styles appear not to explain these excess costs. The mechanisms behind this excess expenditure remain to be elucidated.
PMCID: PMC3851974  PMID: 24044374
(Persisting) frequent attender; High utilizer; Healthcare expenditure; Primary care; General practice; Primary care physician; General practitioner; Linkage study; Reimbursements data; Multimorbidity
25.  Effect of an E-mental Health Approach to Workers' Health Surveillance versus Control Group on Work Functioning of Hospital Employees: A Cluster-RCT 
PLoS ONE  2013;8(9):e72546.
To evaluate an e-mental health (EMH) approach to workers' health surveillance (WHS) targeting work functioning (WF) and mental health (MH) of healthcare professionals in a randomised controlled trial.
Nurses and allied health professionals (N = 1140) were cluster-randomised at ward level to the intervention (IG) or control group (CG). The intervention consisted of two parts: (a) online screening and personalised feedback on impaired WF and MH, followed by (b) a tailored offer of self-help EMH interventions. CG received none of these parts. Primary outcome was impaired WF (Nurses Work Functioning Questionnaire), assessed at baseline and after three and six months. Analyses were performed in the positively screened subgroup (i) and in all participants (ii).
Participation rate at baseline was 32% (NIG = 178; NCG = 188). Eighty-two percent screened positive for at least mild impairments in WF and/or MH (NIG = 139; NCG = 161). All IG-participants (N = 178) received part (a) of the intervention, nine participants (all positively screened, 6%) followed an EMH intervention to at least some extent. Regarding the subgroup of positively screened participants (i), both IG and CG improved over time regarding WF (non-significant between-group difference). After six months, 36% of positively screened IG-participants (18/50) had a relevant WF improvement compared to baseline, versus 28% (32/115) of positively screened CG-participants (non-significant difference). In the complete sample (ii), IG and CG improved over time but IG further improved between three and six months while CG did not (significant interaction effect).
In our study with a full compliance rate of 6% and substantial drop-out leading to a small and underpowered sample, we could not demonstrate that an EMH-approach to WHS is more effective to improve WF and MH than a control group. The effect found in the complete sample of participants is not easily interpreted. Reported results may be useful for future meta-analytic work.
Trial Registration
Dutch Trial Register NTR2786
PMCID: PMC3772000  PMID: 24069148

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